Methods for identifying inhibitors of cytochrome P450RAI

ABSTRACT

A method of identifying a compound which is an inhibitor of the enzyme cytochrome P450RAI is performed by selecting a compound that has retinoid activity in an art recognized assay and includes a benzoic acid, benzoic acid ester, naphthoic acid ester or heteroaryl carboxylic acid or ester moiety, with a partial structure of —A(R 2 )—(CH 2 ) n—COOR   8  where n is 0 and the remaining variables are as described in the specification and claims. Thereafter, a compound having the cytochrome P450RAI inhibitory activity is identified and selected where the compound has the —A(R 2 )—(CH 2 ) 2 —COOR 8  partial structure wherein the variable n is 1 or 2.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional of application Ser. No. 09/963,318,filed on Jun. 7, 2001 now U.S. Pat. No. 6,495,552, which is a divisionalof application Ser. No. 09/672,751 filed on Sep. 28, 2000 now U.S. Pat.No. 6,313,107, which is itself a continuation-in-part of applicationSer. No. 09/651,235, filed Aug. 29, 2000 now U.S. Pat. No. 6,252,090.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is directed to providing, preparing and usingcompounds which inhibit the enzyme cytochrome P450RAI. Moreparticularly, the present invention is directed to selecting andpreparing compounds which inhibit the enzyme cytochrome P450RAI, many ofwhich are derivatives of phenylacetic or heteroarylacetic acid, andusing said compounds for treatment of diseases and conditions which arenormally treated by retinoids.

2. Background Art

Compounds which have retinoid-like activity are well known in the art,and are described in numerous United States and other patents and inscientific publications. It is generally known and accepted in the artthat retinoid-like activity is useful for treating animals of themammalian species, including humans, for curing or alleviating thesymptoms and conditions of numerous diseases and conditions. In otherwords, it is generally accepted in the art that pharmaceuticalcompositions having a retinoid-like compound or compounds as the activeingredient are useful as regulators of cell proliferation anddifferentiation, and particularly as agents for treating skin-relateddiseases, including, actinic keratoses, arsenic keratoses, inflammatoryand non-inflammatory acne, psoriasis, ichthyoses and otherkeratinization and hyperproliferative disorders of the skin, eczema,atopic dermatitis, Darriers disease, lichen planus, prevention andreversal of glucocorticoid damage (steroid atrophy), as a topicalanti-microbial, as skin anti-pigmentation agents and to treat andreverse the effects of age and photo damage to the skin. Retinoidcompounds are also useful for the prevention and treatment of cancerousand precancerous conditions, including, premalignant and malignanthyperproliferative diseases such as cancers of the breast, skin,prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung,larynx, oral cavity, blood and lymphatic system, metaplasias,dysplasias, neoplasias, leukoplakias and papillomas of the mucousmembranes and in the treatment of Kaposi's sarcoma. In addition,retinoid compounds can be used as agents to treat diseases of the eye,including, without limitation, proliferative vitreoretinopathy (PVR),retinal detachment, dry eye and other corneopathies, as well as in thetreatment and prevention of various cardiovascular diseases, including,without limitation, diseases associated with lipid metabolism such asdyslipidemias, prevention of post-angioplasty restenosis and as an agentto increase the level of circulating tissue plasminogen activator (TPA).Other uses for retinoid compounds include the prevention and treatmentof conditions and diseases associated with human papilloma virus (HPV),including warts and genital warts, various inflammatory diseases such aspulmonary fibrosis, ileitis, colitis and Krohn's disease,neurodegenerative diseases such as Alzheimer's disease, Parkinson'sdisease and stroke, improper pituitary function, including insufficientproduction of growth hormone, modulation of apoptosis, including boththe induction of apoptosis and inhibition of T-Cell activated apoptosis,restoration of hair growth, including combination therapies with thepresent compounds and other agents such as Minoxidil^(R), diseasesassociated with the immune system, including use of the presentcompounds as immunosuppressants and immunostimulants, modulation oforgan transplant rejection and facilitation of wound healing, includingmodulation of chelosis. Retinoid compounds have relatively recently beenalso discovered to be useful for treating type II non-insulin dependentdiabetes mellitus (NIDDM).

Several compounds having retinoid-like activity are actually marketedunder appropriate regulatory approvals in the United States of Americaand elsewhere as medicaments for the treatment of several diseasesresponsive to treatment with retinoids. Retinoic acid (RA) itself is anatural product, biosynthesized and present in a multitude of human andmammalian tissues and is known to play an important rule in theregulation of gene expression, tissue differentiation and otherimportant biological processes in mammals including humans. Relativelyrecently it has been discovered that a catabolic pathway in mammals,including humans, of natural retinoic acid includes a step ofhydroxylation of RA catalyzed by the enzyme Cytochrome P450RAI (retinoicacid inducible).

Several inhibitors of CP450RAI have been synthesized or discovered inthe prior art, among the most important ones ketoconazole, liarozole andR116010 are mentioned. The chemical structures of these prior artcompounds are provided below. It has also been noted in the prior art,that administration to mammals, including humans, of certain inhibitorsof CP-450RAI results in significant increase in endogeneous RA levels,and further that treatment with CP450RAI inhibitors, for example withliarozole, gives rise to effects similar to treatment by retinoids, forexample amelioration of psoriasis.

The following publications describe or relate to the above-summarizedrole of CP450RAI in the natural catabolism of RA, to inhibitors ofCP-450RAI and to in vitro and in vivo experiments which demonstrate thatinhibition of CP450RAI activity results in a increases endogeneous RAlevels and potential therapeutic benefits:

-   Kuijpers, et al., “The effects of oral liarozole on epidermal    proliferation and differentiation in severe plaque psoriasis are    comparable with those of acitretin”, British Journal of    Dermatology, (1998) 139: pp 380-389.-   Kang, et al., “Liarozole Inhibits Human Epidermal Retinoid    Acid4-Hydroxylase Activity and Differentially Augments Human Skin    Responses to Retinoic Acid and Retinol In Vivo”, The Journal of    Investigative Dermatology, (August 1996) Vol. 107, No. 2: pp    183-187.-   Van Wauwe, et al., “Liarozole, an Inhibitor of Retinoic Acid    Metabolism, Exerts Retinoid-Mimetic Effects in Vivo”, The Journal of    Pharmacology and Experimental Therapeutics, (1992) Vol. 261, No 2:    pp 773-779.-   De Porre, et al., “Second Generation Retinoic Acid Metabolism    Blocking Agent (Ramba) R116010: Dose Finding in Healthy Male    Volunteers”, University of Leuven, Belgium, pp 30.-   Wauwe, et al., “Ketoconazole Inhibits the in Vitro and in Vivo    Metabolism of All-Trans-Retinoic Acid”, The Journal of Pharmacology    and Experimental Therapeutics, (1988) Vol. 245, No. 2: pp 718-722.-   White, et al., “cDNA Cloning of Human Retinoic Acid-metabolizing    Enzyme (hP450RAI) Identifies a Novel Family of Cytochromes P450    (CYP26)*”, The Journal of Biological Chemistry, (1997) Vol. 272, No.    30, Issue of July 25 pp 18538-18541.-   Hanzlik, et al., “Cyclopropylamines as Suicide Substrates for    Cytochromes P450RAI”, Journal of Medicinal Chemistry (1979), Vol.    22, No. 7, pp 759-761.-   Ortiz de Montellano, “Topics in Biology—The Inactivation of    Cytochrome P450RAI”, Annual Reports in Medicinal Chemistry, (1984),    Chapter 20, pp 201-210.-   Hanzlik, et al. “Suicidal Inactivation of Cytochrome P450RAI by    Cyclopropylamines>Evidence for Cation-Radical Intermediates”, J. Am.    Chem. Soc., (1982), Vol. 104, No. 107, pp. 2048-2052.

In accordance with the present invention several previously known andseveral new compounds are utilized as inhibitors of CP450RAI to providetherapeutic benefit in the treatment or prevention of the diseases andconditions which respond to treatment by retinoids and or which inhealthy mammals, including humans, are controlled by natural retinoicacid. The perceived mode of action of these compounds is that byinhibiting the enzyme CP450RAI that catabolyzes natural RA, endogenousRA level is elevated to a level where desired therapeutic benefits areattained. The chemical structures of certain previously known compoundswhich have been discovered to be inhibitors of the enzyme CP450RAI areprovided in the descriptive portion of this application for patent. Thechemical structures of the novel compounds which are used in the methodsof treatment in accordance with the invention are summarized by Formulas1 through 8 in the Summary Section of this application for patent. Basedon these chemical structures the following art is of interest asbackground to the novel structures.

U.S. Pat. Nos. 5,965,606; 6,025,388; 5,773,594; 5,675,024; 5,663,347;5,045,551; 5,023,341; 5,264,578; 5,089,509; 5,616,712; 5,134,159;5,346,895; 5,346,915; 5,149,705; 5,399,561; 4,980,369; 5,015,658;5,130,335; 4,740,519; 4,826,984; 5,037,825; 5,466,861; WO 85/00806; EP 0130,795; DE 3316932; DE 3708060; Dawson, et al. “Chemistry and Biologyof Synthetic Retinoids”, published by CRC Press, Inc., (1990), pages324-356; are of interest to compounds of Formula 1.

U.S. Pat. Nos. 5,965,606; 5,534,641; 5,663,357; 5,013,744; 5,326,898;5,202,471; 5,391,753; 5,434,173; 5,498,795; 4,992,468; 4,723,028;4,855,320; 5,563,292; WO 85/04652; WO 91/16051; WO 92/06948; EP 0 170105; EP0 286 364; EP0 514 269; EP0 617 020; EP0 619 116; DE 3524199;Derwent JP6072866; Dawson, et al. “Chemistry and Biology of SyntheticRetinoids”, published by CRC Press, Inc., 1990, pages 324-356; are ofinterest to compounds of Formula 2.

Dawson, et al. “Chemistry and Biology of Synthetic Retinoids”, publishedby CRC Press Inc., (1990), pages 324-356; is of interest to compounds ofFormula 3.

U.S. Pat. Nos. 5,965,606; 5,773;594; 5,675,024; 5,663,347; 5,023,341;5,264,578; 5,089,509; 5,149,705; 5,130,335; 4,740,519; 4,826,969;4,833,240; 5,037, 825; 5,466,861; 5,559,248; WO 85/00806; WO 92/06948;WO 95/04036; WO 96/05165; EP 0 098 591; EP 0 170 105; EP 0 176 034; EP0253,302; EP0 303 915; EP0 514 269; EP0 617 020; EP0 619 116; EP 0 661259; DE 3316932; DE 3602473; DE 3715955; UK application GB 2190378;Eyrolles et al., J. Med. Chem., (1994), 37, 1508-1517; Graupner et al.Biochem. and Biophysical Research Communications, (,1991), 1554-1561;Kagechika, et al., J. Med. Chem., (1988), 31, 2182-2192; Dawson, et al.“Chemistry and Biology of Synthetic Retinoids”, published by CRC Press,Inc., (1990), pages 324-356; are of interest to compounds of Formula 4.

U.S. Pat. Nos. 5,965,606; 6,025,388; 5,534,641; 5,663,357; 5,013,744;5,326,898; 5,202,471; 5,391,753; 5,434,173; 5,498,795; 4,992,468;5,723,028; 4,855,320; 5,563,292; WO 85/04652; WO 91/16051; WO 92/06948;EP 0 170 105; EP 0 286 364; EP 0 514 269; EP 0 617 020; EP 0 619 116; DE3524199; Derwent JP6072866; Dawson, et al. “Chemistry and Biology ofSynthetic Retinoids”, published by CRC Press Inc., (1990), pages324-356; are of interest to compounds of Formula 5.

U.S. Pat. Nos. 5,965,606; 6,025,388; 5,534,641; 5,663,357; 5,013,744;5,326,898; 5,202,471; 5,391,753; 5,434,173; 5,498,795; 4,992,468;5,723,028; 4,855,320; 5,563,292; WO 85/04652; WO 91/16051; WO 92/06948;EP 0 170 105; EP 0 286 364; EP 0 514 269; EP 0 617 020; EP 0 619 116; DE3524199; Derwert JP6072866; Dawson, et al. “Chemistry and Biology ofSynthetic Retinoids”, published by CRC Press, Inc., (1990), pages324-356; are of interest to compounds of Formula 6.

U.S. Pat. Nos. 6,048,873; 5,663,347; 5,045,551; 5,023,341; 5,739,338;5,264,578; 5,089,509; 5,616,712; 5,399,561; 4,826,984; 5,037,825; EP 0130 795; DE 3316932; Dawson, et al. “Chemistry and Biology of SyntheticRetinoids”, published by CRC Press, Inc., (1990), pages 324-356; are ofinterest to compounds of Formula 7.

U.S. Pat. Nos. 5,965,606; 5,998,471; 5,773,594; 5,675,024; 5,663,347;5,045,551; 5,023,341; 5,264,578; 5,134,159; 5,346,895; 5,346,915;5,149,705; 5,399,561; 4,980,369; 5,130,335; 4,326,055; 4,539,154;4,740,519; 4,826,969; 4,826,984; 4,833,240; 5,037,825; 5,466,861;5,559,248; WO 85/00806; WO 92/06948; WO 95/04036; WO 96/05165; EP 0 098591; EP 0 130 795; EP 0 176 034; EP 0 253 302; EP 0 303 915; EP 0 514269; EP 0 617 020; EP 0 619 116; EP 0 661 259; DE 3316932; DE 3602473;DE 3708060; DE 3715955; U.K. application GB 2190378; Eyrolles et al., J.Med. Chem., (1994), 37 1508, 1517; Graupner et al., Biochem. andBiophysical Research Communications, (1991) 1554-1561; Kagechika, etal., J. Med. Chem., (1988), 31, 2182-2192; Dawson, et al. “Chemistry andBiology of Synthetic Retinoids”, published by CRC Press Inc., (1990),pages 324-356; are of interest to compounds of Formula 8.

Prior art which is of interest as background to the previously knowncompounds that have been discovered in accordance with the presentinvention to be inhibitors of cytochrome P450RAI, is identified togetherwith the identification of these known compounds.

SUMMARY OF THE INVENTION

In accordance with the present invention novel compounds of Formulas 1through 8 are used as inhibitors of the enzyme cytochrome P450RAI totreat diseases and conditions which are normally responsible totreatment by retinoids, or which are prevented, treated, ameliorated, orthe onset of which is delayed by administration of retinoid compounds orby the mammalian organism's naturally occurring retinoic acid. Thesenovel compounds are shown by Formulas 1

-   -   wherein A is a phenyl or naphthyl group, or heteroaryl selected        from a group consisting of pyridyl, thienyl, furyl, pyridazinyl,        pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and        pyrrazolyl, said phenyl and heteroaryl groups being optionally        substituted with one or two R₂ groups;    -   X is O, S or NR where R is H, alkyl of 1 to 6 carbons or benzyl;    -   Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen        substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons,        cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl        of 3 to 6 carbons, Cl, Br, or I;    -   Z is —C≡C—,        -   —(CR₁═CR₁)_(n′) where n′ is an integer having the value 1-5,        -   —CO—NR₁—,        -   NR₁—CO—;        -   —CO—O—,        -   —O—CO—,        -   —CS—NR₁—,        -   NR₁—CS—,        -   —CO—S—,        -   —S—CO—,        -   —N═N—;    -   R₁ is independently H or alkyl of 1 to 6 carbons;    -   p is an integer having the values of 0 to 4;    -   R₂ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I,        CF₃, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to        6 carbons, or alkylthio of 1 to 6 carbons;    -   R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I,        fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1        to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;    -   m is an integer having the values 0 to 2;    -   R₄ is independently H, alkyl of 1 to 6 carbons, or F;        fluorosubstituted alkyl of 1 to 6 carbons, or halogen;    -   o is an integer having the values of 0 to 2;    -   n is an integer having the values of 0 to 4, and    -   R₈ is H, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl), or a cation        of a pharmaceutically acceptable base.

The novel compounds used in the method of treatment of the presentinvention are also shown in Formula 2

-   -   wherein A is a phenyl or naphthyl group, or heteroaryl selected        from a group consisting of pyridyl, thienyl, furyl, pyridazinyl,        pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and        pyrrazolyl, said phenyl and heteroaryl groups being optionally        substituted with one or two R₂ groups;    -   X is O, S or NR where R is H, alkyl of 1 to 6 carbons or benzyl;    -   Z is —C≡C—,        -   —(CR₁═CR₁)_(n′) where n′ is an integer having the value 1-5,        -   —CO—NR₁—,        -   NR₁—CO—,        -   —CO—O—,        -   —O—CO—,        -   —CS—NR₁—,        -   NR₁—CS—,        -   —CO—S—,        -   —S—CO—,        -   —N═N—;    -   R₁ is independently H or alkyl of 1 to 6 carbons;    -   p is an integer having the values of 0 to 4;    -   R₂ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I,        fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6        carbons, or alkylthio of 1 to 6 carbons;    -   R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I,        fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1        to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;    -   m is an integer having the values 0 to 4;    -   R₅ is H, alkyl of 1 to 6 carbons, fluorosubstituted alkyl of 1        to 6 carbons, benzyl, or lower alkyl or halogen substituted        benzyl;    -   n is an integer having the values of 0 to 4, and    -   R₈ is H, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl), or a cation        of a pharmaceutically acceptable base.

The novel compounds used in the method of treatment of the presentinvention are also shown in Formula 3.

-   -   wherein A is a phenyl or naphthyl group, or heteroaryl selected        from a group consisting of pyridyl, thienyl, furyl, pyridazinyl,        pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and        pyrrazolyl, said phenyl and heteroaryl groups being optionally        substituted with one or two R₂ groups;    -   Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen        substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons,        cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl        of 1 to 6 carbons, Cl, Br, or I;    -   Z is —C≡C—,        -   —(CR₁═CR₁)_(n′) where n′ is an integer having the value 1-5,        -   —CO—NR₁—,        -   NR₁—CO—,        -   —CO—O—,        -   —O—CO—,        -   —CS—NR₁—,        -   NR₁—CS—,        -   —CO—S—,        -   —S—CO—,        -   —N═N—;    -   R₁ is independently H or alkyl of 1 to 6 carbons;    -   p is an integer having the values of 0 to 5;    -   R₂ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I,        fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6        carbons, or alkylthio of 1 to 6 carbons;    -   R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I,        fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1        to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;    -   m is an integer having the values 0 to 2;    -   R₄ is independently H, alkyl of 1 to 6 carbons, or F;        fluorosubstituted alkyl of 1 to 6 carbons, or halogen;    -   o is an integer having the values of 0 to 4;    -   n is an integer having the values of 0 to 4, and    -   R₈ is H, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl), or a cation        of a pharmaceutically acceptable base.

The novel compounds used in the method of treatment of the presentinvention are also shown in Formula 4

-   -   wherein A is a phenyl or naphthyl group, or heteroaryl selected        from a group consisting of pyridyl, thienyl, furyl, pyridazinyl,        pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and        pyrrazolyl, said phenyl and heteroaryl groups being optionally        substituted with one or two R₂ groups;    -   X₁ is 1-imidazolyl, or lower alkyl or halogen substituted        1-imidazolyl, OR, SR, NRR₆ where R is H, alkyl of 1 to 6 carbons        or benzyl;    -   Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen        substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons,        cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl        of 3 to 6 carbons, Cl, Br, or I;    -   Z is —C≡C—,        -   —(CR₁═CR₁)_(n′) where n′ is an integer having the value 1-5,        -   —CO—NR₁—,        -   NR₁—CO—,        -   —CO—O—,        -   —O—CO—,        -   —CS—NR₁—,        -   NR₁—CS—,        -   —CO—S—,        -   —S—CO—,        -   —N═N—;    -   R₁ is independently H or alkyl of 1 to 6 carbons;    -   R₂ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I,        fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6        carbons, or alkylthio of 1 to 6 carbons;    -   R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I,        fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1        to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;    -   m is an integer having the values 0 to 2;    -   R₄ is independently H, alkyl of 1 to 6 carbons, or F;        fluorosubstituted alkyl of 1 to 6 carbons, or halogen;    -   o is an integer having the values of 0 to 4;    -   R₆ is H, lower alkyl, cycloalkyl of 3 to 6 carbons, lower alkyl        substituted cycloalkyl of 3 to 6 carbons;    -   n is an integer having the values of 0 to 4, and    -   R₈ is H, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl), or a cation        of a pharmaceutically acceptable base, with the proviso that        when Y is H, A is phenyl and X₁ is OH then n is 1 to 4.

The novel compounds used in the method of treatment of the presentinvention are also shown in Formula 5

-   -   wherein A is a phenyl or naphthyl group, or heteroaryl selected        from a group consisting of pyridyl, thienyl, furyl, pyridazinyl,        pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and        pyrrazolyl, said phenyl and heteroaryl groups being optionally        substituted with one or two R₂ groups;    -   X is O, S or NR where R is H, alkyl of 1 to 6 carbons,        C₁₋₆-trialkylsilyl or benzyl;    -   Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen        substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons,        cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl        of 3 to 6 carbons, Cl, Br, or I;    -   Z is —C≡C—,        -   —(CR₁═CR₁)_(n′) where n′ is an integer having the value 1-5,        -   —CO—NR₁—,        -   NR₁—CO—,        -   —CO—O—,        -   —O—CO—,        -   —CS—NR₁—,        -   NR₁—CS—,        -   —CO—S—,        -   —S—CO—,        -   —N═N—;    -   R₁ is independently H or alkyl of 1 to 6 carbons;    -   R₂ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I,        fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6        carbons, or alkylthio of 1 to 6 carbons;    -   R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I,        fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1        to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;    -   m is an integer having the values 0 to 3;    -   R₇ is H, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons        or lower alkyl substituted cycloalkyl of 1 to 6 carbons;    -   n is an integer having the values of 1 to 4, and    -   R₈ is H, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl), or a cation        of a pharmaceutically acceptable base.

The novel compounds used in the method of treatment of the presentinvention are also shown in Formula 6

-   -   wherein A is a phenyl or naphthyl group, or heteroaryl selected        from a group consisting of pyridyl, thienyl, furyl, pyridazinyl,        pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and        pyrrazolyl, said phenyl and heteroaryl groups being optionally        substituted with one or two R₂ groups;    -   X₂ is 1-imidazolyl, lower alkyl or halogen substituted        1-imidazolyl, OR₇, SR₇ or NRR₇ where R is H, alkyl of 1 to 6        carbons or benzyl;    -   Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen        substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons,        cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl        of 3 to 6 carbons, Cl, Br, or I;    -   Z is —C≡C—,        -   —(CR₁═CR₁)_(n′) where n′ is an integer having the value 1-5,        -   —CO—NR₁—,        -   NR₁—CO—,        -   —CO—O—,        -   —O—CO—,        -   —CS—NR₁—,        -   NR₁—CS—,        -   —CO—S—,        -   —S—CO—,        -   —N═N—;    -   R₁ is independently H or alkyl of 1 to 6 carbons;    -   R₂ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I,        fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6        carbons, or alkylthio of 1 to 6 carbons;    -   R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I,        fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1        to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;    -   m is an integer having the values 0 to 3;    -   R₇ is H, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons,        lower alkyl substituted cycloalkyl of 3 to 6 carbons or        C₁₋₆-trialkylsilyl.    -   n is an integer having the values of 0 to 4, and    -   R₈ is H, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl), or a cation        of a pharmaceutically acceptable base.

The novel compounds used in the method of treatment of the presentinvention are also shown in Formula 7

-   -   wherein A is a phenyl or naphthyl group, or heteroaryl selected        from a group consisting of pyridyl, thienyl, furyl, pyridazinyl,        pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and        pyrrazolyl, said phenyl and heteroaryl groups being optionally        substituted with one or two R₂ groups;    -   Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen        substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons,        cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl        of 3 to 6 carbons, F, Cl, Br, or I;    -   Z is —C≡C—,        -   —(CR₁═CR₁)_(n′) where n′ is an integer having the value 1-5,        -   —CO—NR₁—,        -   NR₁—CO—,        -   —CO—O—,        -   —O—CO—,        -   —CS—NR₁—,        -   NR₁—CS—,        -   —CO—S—,        -   —S—CO—,        -   —N═N—;    -   R₁ is independently H or alkyl of 1 to 6 carbons;    -   p is an integer having the values of 0 to 5;    -   R₂ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I,        CF₃, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to        6 carbons, or alkylthio of 1 to 6 carbons;    -   R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃,        fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1        to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;    -   m is an integer having the values 0 to 2;    -   R₄ is independently H, alkyl of 1 to 6 carbons, or F;        fluorosubstituted alkyl of 1 to 6 carbons, or halogen;    -   o is an integer having the values of 0 to 4;    -   n is an integer having the values of 0 to 4, and    -   R₈ is H, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl), or a cation        of a pharmaceutically acceptable base.

The novel compounds used in the method of treatment of the presentinvention are also shown in Formula 8

-   -   wherein A is a phenyl or naphthyl group, or heteroaryl selected        from a group consisting of pyridyl, thienyl, furyl, pyridazinyl,        pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and        pyrrazolyl, said phenyl and heteroaryl groups being optionally        substituted with one or two R₂ groups;    -   X₃ is S, or O, C(R₁)₂, or CO;    -   Y₁ is H, lower alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6        carbons, benzyl, lower alkyl substituted cycloalkyl of 3 to 6        carbons;    -   Z is —C≡C—,        -   —(CR₁═CR₁)_(n′) where n′ is an integer having the value 1-5,        -   —CO—NR₁—,        -   NR₁—CO—,        -   —CO—O—,        -   —O—CO—,        -   —CS—NR₁—,        -   NR₁—CS—,        -   —CO—S—,        -   —S—CO—,        -   —N═N—;    -   R₁ is independently H or alkyl of 1 to 6 carbons;    -   R₂ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I,        CF₃, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to        6 carbons, or alkylthio of 1 to 6 carbons;    -   R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃,        fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1        to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;    -   m is an integer having the values 0 to 2;    -   R₄ is independently H, alkyl of 1 to 6 carbons, or F;        fluorosubstituted alkyl of 1 to 6 carbons, or halogen;    -   o is an integer having the values of 0 to 4;    -   n is an integer having the values of 0 to 4, and    -   R₈ is H, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl), or a cation        of a pharmaceutically acceptable base, the compound meeting at        least one of the provisos selected from the group consisting of:        -   Y₁ is cycloalkyl,        -   when Y₁ is not cycloalkyl then X₃ is O or S and n is 1,        -   when Y₁ is not cycloalkyl then X₃ is CO, and n is 1,        -   when Y1 is not cycloalkyl then X₃ is CO and the moiety A is            substituted with at least one F group.

In accordance with the invention the novel compounds of Formula 1through Formula 8 as well as the previously known compounds disclosedbelow in the specification are used for the prevention or treatment ofdiseases and conditions in mammals, including humans, those diseases orconditions that are prevented, treated, ameliorated, or the onset ofwhich is delayed by administration of retinoid compounds or by themammalian organism's naturally occurring retinoic acid. Because thecompounds act as inhibitors of the breakdown of retinoic acid, theinvention also relates to the use of the compounds of Formula 1 throughFormula 8 in conjunction with retinoic acid or other retinoids. In thisregard it is noted that retionoids are useful for the treatment ofskin-related diseases, including, without limitation, actinic keratoses,arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis,ichthyoses and other keratinization and hyperproliferative disorders ofthe skin, eczema, atopic dermatitis, Darriers disease, lichen planus,prevention and reversal of glucocorticoid damage (steroid atrophy), as atopical anti-microbial, as skin anti-pigmentation agents and to treatand reverse the effects of age and photo damage to the skin. Theretinoids are also useful for the prevention and treatment of metabolicdiseases such as type II non-insulin dependent diabetes mellitus (NIDDM)and for prevention and treatment of cancerous and precancerousconditions, including, premalignant and malignant hyperproliferativediseases such as cancers of the breast, skin, prostate, cervix, uterus,colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood andlymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias andpapillomas of the mucous membranes and in the treatment of Kaposi'ssarcoma. Retinoids can also be used as agents to treat diseases of theeye, including, without limitation, proliferative vitreoretinopathy(PVR), retinal detachment, dry eye and other corneopathies, as well asin the treatment and prevention of various cardiovascular diseases,including, without limitation, diseases associated with lipid metabolismsuch as dyslipidemias, prevention of post-angioplasty restenosis and asan agent to increase the level of circulating tissue plasminogenactivator (TPA). Other uses for retinoids include the prevention andtreatment of conditions and diseases associated with human papillomavirus (HPV), including warts and genital warts, various inflammatorydiseases such as pulmonary fibrosis, ileitis, colitis and Krohn'sdisease, neurodegenerative diseases such as Alzheimer's disease,Parkinson's disease and stroke, improper pituitary function, includinginsufficient production of growth hormone, modulation of apoptosis,including both the induction of apoptosis and inhibition of T-Cellactivated apoptosis, restoration of hair growth, including combinationtherapies with the present compounds and other agents such asMinoxidil®, diseases associated with the immune system, including use ofthe present compounds as immunosuppressants and immunostimulants,modulation of organ transplant rejection and facilitation of woundhealing, including modulation of chelosis.

This invention also relates to a pharmaceutical formulation comprisingone or more compounds of Formula 1 through Formula 8 or one or more ofthe previously known compounds disclosed below in the specification, inadmixture with a pharmaceutically acceptable excipient, said formulationbeing adapted for administration to a mammal , including a human being,to treat or alleviate the conditions which were described above astreatable by retinoids, or which are controlled by or responsive to theorganism's native retinoic acid. These formulations can also beco-administered with retinoids to enhance or prolong the effects ofmedications containing retinoids or of the organism's native retinoicacid.

The present invention also relates to a method of providing a compoundwhich is an inhibitor of the enzyme cytochrome P450RAI, wherein themethod of providing the cytochrome P450RAI inhibitory compoundcomprises:

-   -   identifying a compound that has activity as a retinoid in any of        the art recognized assays which demonstrate retinoid-like        activity, the retinoid compound having a formula such that it        includes a benzoic acid, benzoic acid ester, naphthoic acid,        naphthoic acid ester or heteroaryl carboxylic acid or ester        moiety, with a partial structure of —A(R₂)—(CH₂)_(n)—COOR₈ where        the symbols are defined as in Formulas 1 through 8, and where n        is 0, and    -   selecting a compound that is a homolog of the previously        identified retinoid compound where in the formula of the homolog        n is 1 or 2, preferably 1. Said homolog, if it is not a        previously known compound can be prepared by homologation        procedures well known to the synthetic organic chemist, such as        for example the well known Arndt-Eistert synthesis.        Alternatively, said homologs can be prepared by any of the        applicable synthetic processes illustrated below for the        preparation of the novel compounds of Formulas 1 through 8        wherein the symbol n represents the integral 1 (one).

BRIEF DESCRIPTION OF THE DRAWING FIGURE

FIG. 1 is a schematic representation of the P450RAI cell based assayutilized to evaluate the ability of the compounds of the invention toinhibit the Cytochrome P450RAI enzyme.

BIOLOGICAL ACTIVITY, MODES OF ADMINISTRATION

P450RAI-1 Cell-Based Inhibitor Assay:

FIG. 1 shows a schematic diagram of the P450RAI-1 cell based assay.P450RAI-1 stably transfected HeLa cells are maintained in 100 millimolartissue culture dishes in Modified Eagle's Medium (MEM) containing 10%Fetal Bovine Serum (FBS) and 100 μg/ml hygromycin. Exponentially growingcells are harvested by incubating in trypsin. Cells are then washed with1× Phosphate Buffered Saline (PBS) and plated in a 48-well plate at5×10⁵ cells in 0.2 ml MEM medium containing 10% FBS and 0.05 μCi [³H]-RAin the presence or absence of increasing concentrations of the testcompounds. The compounds are diluted in 100% DMSO and then added intriplicate wells at either 10, 1 or 0.1 μM final concentration. As apositive control for RA metabolism inhibition, cells are also incubatedwith ketoconazole at 100, 10 and 1 μM. Cell are incubated for 3 hours at37° C. The retinoids are then extracted using the procedure of Bligh etal. (1959) Canadian Journal of Biochemistry 37, 911-917, modified byusing methylenechloride instead of chloroform. The publication Bligh etal. (1959) Canadian Journal of Biochemistry 37, 911-917 is specificallyincorporated herein by reference. The water soluble radioactivity isquantified using β-scintillation counter. IC₅₀ values represent theconcentration of inhibitor required to inhibit all-trans-RA metabolismby 50 percent and are derived manually from log-transformed data. TheIC₅₀ values obtained in this assay for several novel compounds used inaccordance with the invention are disclosed in Table 1 below. The IC₅₀values obtained in this assay for several previously known compounds thecythochrome P450RAI inhibitory activity of which has been discovered inaccordance with the present invention, are disclosed in Table 1A below.

Assays of Retinoid-like or Retinoid Antagonist and Inverse Agonist-like

Biological Activity

Assays described below measure the ability of a compound to bind to,and/or activate various retinoid receptor subtypes. When in these assaysa compound binds to a given receptor subtype and activates thetranscription of a reporter gene through that subtype, then the compoundis considered an agonist of that receptor subtype. Conversely, acompound is considered an antagonist of a given receptor subtype if inthe below described co-tranfection assays the compound does not causesignificant transcriptional activation of the receptor regulatedreporter gene, but nevertheless binds to the receptor with a K_(d) valueof less than approximately 1 micromolar. In the below described assaysthe ability of the compounds to bind to RAR_(α), RAR_(β), RAR_(γ),RXR_(α), RXR_(β) and RXR_(γ) receptors, and the ability or inability ofthe compounds to activate transcription of a reporter gene through thesereceptor subtypes can be tested.

As far as specific assays are concerned, a chimeric receptortransactivation assay which tests for agonist-like activity in theRAR_(α), RAR_(β), and RAR_(γ), receptor subtypes, and which is based onwork published by Feigner P. L. and Holm M. (1989) Focus, 112 isdescribed in detail in U.S. Pat. No. 5,455,265. The specification ofU.S. Pat. No. 5,455,265 is hereby expressly incorporated by reference.The numeric results obtained with several preferred novel compounds usedin accordance with the invention in this assay are shown below inTable 1. These data demonstrate that generally speaking the compounds ofFormulas 1 through 8, are not agonists (or only weak agonists) of RARretinoic receptors, and also that they do not bind, or in some casesbind only weakly to RAR retinoid receptors.

A holoreceptor transactivation assay and a ligand binding assay whichmeasure the antagonist/agonist like activity of the compounds used inaccordance with the invention, or their ability to bind to the severalretinoid receptor subtypes, respectively, are described in published PCTApplication No. WO WO93/11755 (particularly on pages 30-33 and 37-41)published on Jun. 24, 1993, the specification of which is alsoincorporated herein by reference. A detailed experimental procedure forholoreceptor transactivations has been described by Heyman et al. Cell68, 397-406, (1992); Allegretto et al. J. Biol. Chem. 268, 26625-26633,and Mangelsdorf et al. The Retinoids: Biology, Chemistry and Medicine,pp 319-349, Raven Press Ltd., New York, which are expressly incorporatedherein by reference. The results obtained in this assay are expressed inEC₅₀ numbers, as they are also in the chimeric receptor transactivationassay. The results of ligand binding assay are expressed in K_(d)numbers. (See Cheng et al. Biochemical Pharmacology Vol. 22 pp3099-3108, expressly incorporated herein by reference.)

The results if the ligand binding assay for several preferred novelcompounds used in accordance with the invention are included in Table 1.In the holoreceptor transactivation assay, tested for RXR_(α), RXR_(β),and RXR_(γ) receptors, the novel compounds are, generally speaking,entirely devoid of activity, demonstrating that the novel compounds donot act as RXR agonists.

TABLE 1 P450RAI RAR INHIBITION DATA Compound General TableEC₅₀/(EFFICACY)/K_(d)nM INTACT HELA # Formula #¹ α β γ IC₅₀ μM 110 2 3NA 74 262 >10 (44) (42) 2058 409 >10 K 112 2 3 NA 335 NA >10 (37) 5853704 685 3 4 5 280 4.8 9.8 3 (28) (54) (52) 145 0.8 158 114 2 3 NA NANA >10 >10 K >10 K >10 K 108 2 3 6.6 283 141 >10 (15) (36) (10) 21 K 54713 K 116 2 3 NA WA NA >10 3269 732 886 77 2 3 NA WA NA >10 2207 225 1678 2 3 NA NA NA >10 >10 K >10 K >10 K 40 1 2 33 1.2 6.8 1.7 (207) (126)(140) 69 1.3 363 42 1 2 NA NA NA 0.19 15 K 3636 >10 K 28 8 9 NA NA NA0.34 21 K 4272 >10 K 70 2 3 NA NA NA >10 >10 K >10 K >10 K 69 2 3 313 1252.6 >10 (10) (50) (31) 469 133 501 73 2 3 WA 22.5 91 >10 (39) (24) 48626 351 74 2 3 NA NA NA 3.5 11 K 14 K >10 K 30 8 9 14 2.2 84 0.28 44 1 249 1.7 7.5 0.27 (138) (100) (116) 37 1.9 392 82 2 3 NA NA NA >10 >10K >10 K >10 K 81 2 3 NA 490 183 >10 (80) (67) 4210 846 1058 89 2 3 26826 12 >10 (20) (50) (46) 3407 980 475 90 2 3 NA NA NA 0.95 >10 K >10K >10 K 94 2 3 NA NA NA >10 >10 K >10 K >10 K 93 2 3 4821 20 10 >10(114) (39) (55) 3450 554 358 5 8 9 NA 11 NA 0.55 (36) 9148 2815 >10 K 84 5 NA 363 NA 0.4 (96) 10 K 3781 25 K 86 2 3 NA NA NA 1.4 >10 K >10K >10 K 85 2 3 976 3.5 2.5 >10 (60) (77) (65) 1861 240 302 98 2 3 NA NANA 0.8 13 4 5 NA 3.2 116 3.1 (6.6) (9) 10 8 9 57 0.3 6 0.7 (146) (86)(94) 36 8 9 13 K 4896 492 0.033 38 8 9 10 K 5317 2884 0.025 34 8 9 61.515 2.5 0.13 119 6 7 >10 K >10 K >10 K 0.4 121 6 7 >10 K >100 K >100 K0.18 46 8 9 >10 K >10 K >10 K 2.2 20 8 9 >10 18 4 5 1.1 32 8 9 27 K 422513 K 0.18 139 4 5 0.05 22 3 4 1.6 24 3 4 3 137 4 5 0.1 26 4 5 10 127 6 70.4 126 6 7 0.09 48 1 2 0.03 50 1 2 0.014 52 1 2 0.05 54 1 2 0.022 62 78 >10 56 8 9 0.13 134 6 7 5 58 1 2 0.18 60 1 2 1.6 143 0.8 145 0.2

Table 1A below provides data similar to those provided in Table 1, forcertain previously known compounds which have been discovered inaccordance with the present invention to be useful as inhibitors ofcytochrome P450RAI. These compounds are shown by Formula A through O andhave compounds numbers 201 through 247.

TABLE 1A P450RAI Com- RAR INHIBITION DATA pound GeneralEC₅₀/(EFFICACY)/K_(d)nM INTACT HELA # Formula α β γ IC₅₀ μM 201 A >10K >10 K 180 0.52 300 (12) (24) 90 1105 4391 202 A 0.6 203 C 0.62 204 C0.7 205 C 1 206 C 1.8 207 D 1.2 208 D 1 209 E 1.7 210 A 89 18 15 10 (25)(122) (61) 10000 2891 10000 211 E 1.5 212 G 7 214 E 1.9 215 A 6.2 216 D3.3 217 G 6.3 218 D 3.4 219 G 3.2 220 C 1 221 C >10 222 F >10 223 F >10224 C 5.5 225 C >10 226 C >10 227 C 1.3 228 C 6 229 G 1.6 230 D 5.1 231K 4.1 232 D 4.2 233 M 1.3 234 M 4.7 235 E 7 236 F 5.5 237 J 6.8 238 A7.2 240 B 3 241 N 5.5 242 I 5.8 243 L 7.4 244 G 5.1 245 H 3.3 246 J 3.1247 O 10

Topical Skin Irritation Tests

As is known the topical retinoid all-trans-retinoic acid (ATRA) and oralretinoids such as 13-cis RA and etretinate are known to inducesubstantial skin irritation in humans. This irritation is a directresult of activation of the RAR nuclear receptors. Analysis of retinoidtopical irritation is also a highly reproducible method of determiningin vivo retinoid potency. The SKH1-hrBR or hairless mouse provides aconvenient animal model of topical irritation, since retinoid-inducedskin flaking and abrasion can be readily scored by eye (Standeven etal., “Specific antagonist of retinoid toxicity in mice.” Toxicol. Appl.Pharmacol., 138:169-175, (1996); Thacher, et al., “Receptor specificityof retinoid-induced hyperplasia. Effect of RXR-selective agonists andcorrelation with topical irritation”. J. Pharm. Exp. Ther., 282:528-534,(1997)). As is demonstrated below the topical application of P450RAIinhibitors in accordance with the present invention also causes anincrease in the endogenous levels of ATRA that results in ATRA-inducedirritation in skin of hairless mice. The attached data table disclosesthe retinoid-mimetic effects of some P450RAI inhibitor compounds inaccordance with the present invention on the skin of hairless mice.

Methods

Female hairless mice (Crl:SKH1-hrBR), 5-7 weeks old, were obtained fromCharles River Breeding Labs (Wilmington, Mass.). Animals were about 6weeks old at the start of the experiments. Food (Purina Rodent Chow5001) and reverse osmosis water were provided ad libitum. Mice werehoused individually throughout the dosing period. In some experiments,mice that fit within a defined weight range, e.g., 21-25 g, wereselected from the available stock and then randomly assigned to thevarious treatment groups, using body weight as the randomizationvariable.

The compounds to be tested were dissolved in acetone for application tothe backs of the mice.

Mice were treated topically on the back in a volume of 4.0 ml/kg(0.07-0.12 ml) adjusted daily so as to deliver a fixed dose of testcompound per g body weight. Doses are disclosed as nmol/25 g.

Unless indicated otherwise, mice were treated with retinoids once dailyon days 1 through 5 and observed on days 2, 3, 4, 5, 6, 7 and 8.

The mice were weighed daily and the dorsal skin was graded daily usingseparate semi-quantitative scales to determine flaking and abrasion.These flaking and abrasion scores were combined with weight change (ifany) to create a cutaneous toxicity score (Blackjack score).

Cutaneous Toxicity Score

A visual grading scale was used for characterizing topical irritation ona daily basis. The grading scale used is as follows:

Flaking Abrasions 0 = none 0 = none 1 = slight (small flakes, <50% 1 =slight (one or two abrasions coverage) with a light pink color) 2 = mild(small flakes, 50% 2 = mild (several abrasions with a coverage) pinkcolor) 3 = moderate (small flakes, >50% 3 = moderate (one or two deepcoverage & large flakes, <25% abrasions with red color, <25% coverage)coverage) 4 = severe (small flakes, >50% 4 = severe (multiple deepabrasions coverage & large flakes, 25-50% with red color, >25% coverage)coverage) 5 = very severe (large flakes, >50% coverage)Topical Toxicity Score

The flaking and abrasion observations were combined with body weightobservations to calculate a single, semiquantitative topical orcutaneous “toxicity score” as detailed below. The toxicity score (alsoknown as “blackjack score” since the theoretical maximum is 21) takesinto account the maximal severity, and the time of onset of skin flakingand abrasions and the extent of weight between the first and last daysof the experiment. Below are listed the seven numerical components ofthe toxicity score and an explanation of how those values are combinedto calculate the toxicity score.

1. Flaking-Maximal Severity: Highest flaking score attained duringobservation period. 2. Flaking-Day of Onset of grade 2 or worse: 0 - >8days 1 - day 8 2 - day 6 or 7 3 - day 4 or 5 4 - day 2 or 3 3.Flaking-Average Severity: Flaking severity scores are summed and dividedby the number of observation days. 4. Abrasion-Maximal Severity: Highestabrasion score attained during observation period. 5. Abrasion-Day ofOnset of grade 2 or worse: Same scale as (2) above. 6. Abrasion-AverageSeverity: Abrasion severity scores are summed and divided by the numberof observation days. 7. Systemic Toxicity (weight loss): 0 - <1 g 1 - 1to 2 g 2 - 2 to 4 g 3 - 4 to 6 g 4 - >6 g or deadCalculation of Composite Flaking Score

Flaking onset score (2) and average severity score (3) are summed anddivided by two. The quotient is added to the maximal severity score (1).Composite flaking scores are calculated for each individual animal in agroup, averaged, and rounded to the nearest integer. Values can rangefrom 0-9.

Calculation of Composite Abrasion Score

Abrasion onset score (5) and average severity score (6) are summed anddivided by two. The quotient is added to the maximal severity score (4).Composite abrasion scores are calculated for each individual animal in agroup, averaged and rounded to the nearest integer. Values can rangefrom 0-8.

Calculation of Toxicity Score

Composite flaking score, composite abrasion score, and systemic toxicityscore are summed to give the “toxicity score.” Toxicity scores arecalculated for each individual animal in a group, averaged, and roundedto the nearest integer. Values can range from 0-21 and are expressed inTable 1B below as the mean±SD of the values for a group.

Calculation of Percentage Change in Body Weight

The body weight at the time of the last weighing (day 8, 11, or 12) wassubtracted from the initial body weight. The difference was divided bythe initial body weight, multiplied by 100%, and rounded to the nearestinteger. Values were calculated for each individual animal and the meanand standard deviation for each group are shown.

TABLE 1B Cutaneous Toxicity Score (Blackjack Score) 100 300 1000Compound No. nmole nmole nmole 5 0 6 ± 3 15 1 ± 1 5 ± 2 36 1 ± 1 11 ± 0 38 1 ± 1 10 ± 1  8 5 ± 2 8 ± 3 12 ± 1  22 0 ± 0 0 ± 0 1 ± 1 137 1 ± 1 1± 1 5 ± 2 48 1 ± 1 3 ± 1 7 ± 2 50 1 ± 0 3 ± 2 8 ± 2 58 0 ± 0 0 ± 0 0 ± 0131 1 ± 1 0 ± 1 1 ± 1 127 0 ± 0 0 ± 0 0 ± 0 18 0 ± 0 5 ± 2 10 ± 2  247 1± 0 2 ± 1 6 ± 1Modes of Administration

The compounds used in the methods of treatment of this invention may beadministered systemically or topically, depending on such considerationsas the condition to be treated, need for site-specific treatment,quantity of drug to be administered, and numerous other considerations.Thus, in the treatment of dermatoses, it will generally be preferred toadminister the drug topically, though in certain cases such as treatmentof severe cystic acne or psoriasis, oral administration may also beused. Any common topical formulation such as a solution, suspension,gel, ointment, or salve and the like may be used. Preparation of suchtopical formulations are well described in the art of pharmaceuticalformulations as exemplified, for example, by Remington's PharmaceuticalScience, Edition 17, Mack Publishing Company, Easton, Pa. For topicalapplication, the compounds could also be administered as a powder orspray, particularly in aerosol form. If the drug is to be administeredsystemically, it may be confected as a powder, pill, tablet or the likeor as a syrup or elixir suitable for oral administration. Forintravenous or intraperitoneal administration, the compound will beprepared as a solution or suspension capable of being administered byinjection. In certain cases, it may be useful to formulate thesecompounds by injection. In certain cases, it may be useful to formulatethese compounds in suppository form or as extended release formulationfor deposit under the skin or intramuscular injection.

Other medicaments can be added to such topical formulation for suchsecondary purposes as treating skin dryness; providing protectionagainst light; other medications for treating dermatoses; medicamentsfor preventing infection, reducing irritation, inflammation and thelike.

Treatment of dermatoses or any other indications known or discovered tobe susceptible to treatment by retinoic acid-like compounds, or tocontrol by naturally occurring retinoic acid will be effected byadministration of the therapeutically effective dose of one or morecompounds used in accordance with the instant invention. A therapeuticconcentration will be that concentration which effects reduction of theparticular condition, or retards its expansion. In certain instances,the compound potentially may be used in prophylactic manner to preventonset of a particular condition.

A useful therapeutic or prophylactic concentration will vary fromcondition to condition and in certain instances may vary with theseverity of the condition being treated and the patient's susceptibilityto treatment. Accordingly, no single concentration will be uniformlyuseful, but will require modification depending on the particularitiesof the disease being treated. Such concentrations can be arrived atthrough routine experimentation. However, it is anticipated that in thetreatment of, for example, acne, or similar dermatoses, that aformulation containing between 0.01 and 1.0 milligrams per milliliter offormulation will constitute a therapeutically effective concentrationfor total application. If administered systemically, an amount between0.01 and 5 mg per kg of body weight per day would be expected to effecta therapeutic result in the treatment of many diseases for which thesecompounds are useful.

In some applications pharmaceutical formulations containing theCP-450RAI inhibitory compounds may be co-administered with formulationscontaining retinoids. In such cases the dose of the cytochrome P450RAIinhibitors compounds is in the range of 0.01 and 5 mg per kg body weightper day.

General Embodiments and Synthetic Methodology

Definitions

The term alkyl refers to and covers any and all groups which are knownas normal alkyl and branched-chain alkyl. Unless specified otherwise,lower alkyl means the above-defined broad definition of alkyl groupshaving 1 to 6 carbons in case of normal lower alkyl, and 3 to 6 carbonsfor lower branch chained alkyl groups. A pharmaceutically acceptablesalt may be prepared for any compound used in accordance with theinvention having a functionality capable of forming a salt, for examplean acid functionality. A pharmaceutically acceptable salt is any saltwhich retains the activity of the parent compound and does not impartany deleterious or untoward effect on the subject to which it isadministered and in the context in which it is administered.

Pharmaceutically acceptable salts may be derived from organic orinorganic bases. The salt may be a mono or polyvalent ion. Of particularinterest are the inorganic ions, sodium, potassium, calcium, andmagnesium. Organic salts may be made with amines, particularly ammoniumsalts such as mono-, di- and trialkyl amines or ethanol amines. Saltsmay also be formed with caffeine, tromethamine and similar molecules.Where there is a nitrogen sufficiently basic as to be capable of formingacid addition salts, such may be formed with any inorganic or organicacids or alkylating agent such as methyl iodide. Preferred salts arethose formed with inorganic acids such as hydrochloric acid, sulfuricacid or phosphoric acid. Any of a number of simple organic acids such asmono-, di- or tri- acid may also be used.

Some compounds used in accordance with the present invention may havetrans and cis (E and Z) isomers. Unless specific orientation ofsubstituents relative to a double bond or a ring is indicated in thename of the respective compound, and/or by specifically showing in thestructural formula the orientation of the substituents relative to thedouble bond or ring the invention covers trans as well as cis isomers.

Some of the compounds used in accordance with the present invention maycontain one or more chiral centers and therefore may exist inenantiomeric and diastereomeric forms. The scope of the presentinvention is intended to cover all isomers per se, as well as mixturesof cis and trans isomers, mixtures of diastereomers and racemic mixturesof enantiomers (optical isomers) as well. A bond drawn with a wavy lineindicates that the carbon to which the bond is attached can be in any ofthe applicable possible configurations.

General Synthetic Methodology

The novel compounds used in accordance with the invention areencompassed by the general Formulas 1 through 8 provided above. Thepreviously known compounds the cytochrome P450RAI activity of which hasbeen discovered in accordance with the present invention are identifiedbelow, and references are provided which enable their preparation by oneof ordinary skill in the art of synthetic organic chemistry. In each ofthese formulas a linker or tethering group designated Z covalentlyconnects an aromatic or heteroaromatic moiety designatedA(R₂)—(CH₂)_(n)—COOR₈ and another cyclic moiety which in accordance withthese formulas is a substituted phenyl, substitutedtetrahydronaphthalene, substituted chroman, thiochroman,tetrahydroquinoline or tetrahydroisoquinoline moiety. Generally speakinga compound such as X₄—A(R₂)—(CH₂)_(n)—COOR₈ is commercially available,or can be made in accordance with the chemical literature, or with suchmodification of known chemical processes which are within the skill ofthe practicing organic chemist. The group X₄ represents a reactivegroup, which is suitable for coupling the X₄₋A(R₂)—(CH₂)_(n)—COOR₈compound to a derivative of the substituted phenyl, substitutedtetrahydronaphthalene, substituted chroman, thiochroman,tetrahydroquinoline or tetrahydroisoquinoline moiety so that as a resultof the coupling the linker or tether moiety Z is formed. In manyinstances the group X₄ is a leaving group such as halogen, ortrifluoromethanesulfonyloxy, or a group capable of participating in aWittig or Horner Emmons reaction. In some instances the group X₄ is anethynyl group capable of undergoing a coupling reaction with a leavinggroup (such as a halogen or a trifluoromethanesulfonyloxy group)attached to the substituted phenyl, substituted tetrahydronaphthalene,substituted chroman, thiochroman, tetrahydroquinoline ortetrahydroisoquinoline moiety. The group X₄ can also represent an OH oran NH₂ group that forms an ester (COO) or amide (CONH) linker,respectively, when reacted with an activated carboxyl derivative of thesubstituted phenyl, substituted tetrahydronaphthalene, substitutedchroman, thiochroman, tetrahydroquinoline or tetrahydroisoquinolinemoiety. Examples for the compounds of formula X₄₋A(R₂)—(CH₂)_(n)—COOR₈are provided in the specific examples below. Further examples where theX₄ group is halogen are ethyl 4-iodobenzoate, ethyl 6-iodonicotinate,ethyl 5-iodofuran-3-carboxylate, ethyl 5-iodothiophen-3-carboxylate,ethyl 5-iodofuran-2-carboxylate, ethyl5-iodothiophen-2-carboxylate, andanalogous halogenated derivatives of the respective pyridazine, pyrazineand other heteroaryl carboxylic acid esters. The analogous aryl and andheteroaryl hydroxyl compounds and amines, wherein the halogen of theabove-listed compounds is replaced by OH or NH₂ respectively, also serveas additional examples for the reagents of the formulaX₄—A(R₂)—(CH₂)_(n)—COOR₈. In these examples X₄ is OH or NH₂,respectively.

Still further in accordance with the general synthetic methodology toprovide the compounds of Formulas 1 through 8 a derivative of thesubstituted phenyl, substituted tetrahydronaphthalene, substitutedchroman, thiochroman, tetrahydroquinoline or tetrahydroisoquinolinemoiety is synthesized first, having a covalently attached X₅ group. TheX₅ group reacts with the X₄ group of the reagentX₄—A(R₂)—(CH₂)_(n)—COOR₈ to form the linker designated Z in Formulas 1through 8. The X₅ group is one that is capable of participating in acatalyzed coupling reaction, (such as an ethynyl group when X₄ is aleaving group), or a leaving group (such as halogen ortrifluoromethanesulfonyloxy when X₄ is an ethynyl group), or anactivated carboxylic acid function (when X₄ is OH or NH₂). The X₅ groupcan also be an OH, SH or NH₂ group when the X₄ group is an activatedcarboxylic acid function. Specific examples for substituted phenyl,substituted tetrahydronaphthalene, substituted chroman, thiochroman,tetrahydroquinoline or tetrahydroisoquinoline intermediates having an X₅functionality are provided below, and are also available in the chemicalscientific and patent literature. Generally speaking, for reagents andreactions covalently joining a substituted tetrahydronaphthalene,substituted chroman, thiochroman, or tetrahydroquinoline intermediatewith a substituted aryl or heteroaryl group, such asX₄—A(R₂)—(CH₂)_(n)—COOR₈, to form a compound including the linkerdesignated Z, reference is made to U.S. Pat. Nos. 5,648,503; 5,723,666and 5,952,345 the specification of each of which are expresslyincorporated herein by reference.

The substituted phenyl, tetrahydronaphthalene, chroman, thiochroman,tetrahydroquinoline or tetrahydroisoquinoline moiety of the novelcompounds used in accordance with the invention are derivatized in amanner to include the specific substituents (such as for example thecycloalkyl substituents) encompassed within the scope of the invention,either before or after the—A(R₂)—(CH₂)_(n)—COOR₈ moiety has beenattached and the linker Z has formed, as illustrated by the belowdescribed specific examples. The —(CH₂)_(n)—COOR₈ moiety of thecompounds of Formulas 1 through 8 can be modified in order to obtainstill further novel compounds. One such modification is saponificationof compounds where the R₈ group is an alkyl or —CH₂O(C₁₋₆-alkyl) group.Another modification is esterification of the carboxylic acid functionwhen the R₈ group is H or a cation. Such saponification andesterification reactions are well known in the art and within the skillof the practicing organic chemist. Still another modification of thecompounds used in accordance with the invention (or of the intermediatesX₄—A(R₂)—(CH₂)_(n)—COOR₈, or of precursors to these intermediates) isthe homologation of the (CH₂)_(n) group. The latter can be accomplished,for example, by the well known Arndt-Eistert method of homologation, orother known methods of homologation.

The previously known compounds which have been discovered to beinhibitors of cythochrome P450RAI and which are used in accordance withthe present invention are made, generally speaking, pursuant to theteachings of a patent or publication which is identified in connectionwith each of the known compounds. These patents or publications areincorporated by reference in the present specification.

The synthetic procedure of homologation that may be utilized forproviding a compound having the partial structure of—A(R₂)—(CH₂)_(n)—COOR₈ where n is 1, or 2 (one or two), preferably 1(one), can be one of the several known procedures of homologation ofcarboxylic acids or esters, such as the Arndt-Eistert procedure that isdescribed inter alia in March, Advanced Organic Chemistry: Reactions,Mechanisms, and Structure, pages 809-810, McGraw-Hill Publishers, 1968,incorporated herein by reference. Alternatively the homologs of thepartial structure of —A(R₂)—(CH₂)_(n)—COOR₈ are synthesized inaccordance with the synthetic schemes disclosed herein in connectionwith the preparation of the novel compounds.

Specific Embodiments

With reference to the symbol A in Formulas 1 through 8, the preferrednovel compounds used in accordance with the present invention are thosewhere A is phenyl, naphthyl, pyridyl, thienyl or furyl. Even morepreferred are compounds where A is phenyl. As far as substitutions onthe A (phenyl) and A (pyridyl) groups are concerned, compounds arepreferred where the phenyl group is 1,4 (para) substituted and where thepyridine ring is 2,5 substituted. (Substitution in the 2,5 positions inthe “pyridine” nomenclature corresponds to substitution in the6-position in the “nicotinic acid” nomenclature.) In the presentlypreferred novel compounds used in accordance with the invention eitherthere is no R₂ substituent on the A group, or the R₂ substituent ispreferably a fluoro group that is preferably located on the aromaticcarbon adjacent (ortho) to the carbon bearing the —(CH₂)_(n)—COOR₈group.

As far as the —(CH₂)_(n)—COOR₈ is concerned the use of novel compoundsis preferred where n is 0, 1 or 2, and even more preferred where n is 1.In Formulas 5 and 8 only compounds where n is 1 or 2 are preferred, withn=1 being most preferred. For the R₈ group H, lower alkyl of 1 to 3carbons, and —CH₂O(C₁₋₆-alkyl) groups are preferred, as well as thepharmaceutically acceptable salts of the free acids when R₈ is H. Amongthe lower alkyl and —CH₂O(C₁₋₆-alkyl) groups ethyl and OCH₂CH₃,respectively, are presently most preferred.

The linker group Z in all of the novel compounds used in accordance withthe invention is preferably ethynyl (—C≡C—), ester (CO—O), ethenyl,(—CR₁═CR₁—) or amide (CONR₁). Among these the ethynyl (—C≡C—) and ester(CO—O) linkers are most preferred. Moreover, preferably the linker Z isattached to the 6 position in Formula 1, to the 4 position in Formula 2,to the 6 position in Formula 3, to the 6 position in Formula 4, to the 4position in Formula 5, to the 4 position in Formula 6, to the 6 positionin Formula 7, and to the 6 position in Formula 8. These positions areindicated by arabic numerals in Formulas 1 through 8.

The R₁ group substituting the non-aromatic rings in Formulas 1, 3, 4, 7and 8 is preferably alkyl, more preferably alkyl of 1 to 3 carbons, andmost preferably methyl. The R₁ group substituting the cyclopropane ringin Formulas 1, 2, 3 and 7 is preferably non-existent (p is 0), or isalkyl of 1 to 3 carbons, even more preferably methyl.

The X group in Formulas 1 and 5 is preferably O, and in Formula 2 X ispreferably O or NR.

The X₁ group in Formula 4 is preferably 1-imidazolyl, substituted1-imidazolyl, or NRR₆, where R₆ is preferably cyclopropyl orbranched-chain alkyl. The X₂ group in Formula 6 is preferably1-imidazolyl or substituted 1-imidazolyl.

The X₃ group in Formula 8 is preferably O or C═O.

The Y group is preferably H, lower alkyl of 1 to 3 carbons, cycloalkyl,lower alkyl substituted cycloalkyl, or halogen. Among these, H, Cl, andcyclopropyl are most preferred.

The Y1 group of Formula 8 is preferably H, lower alkyl of 1 to 3carbons, cycloalkyl, or lower alkyl substituted cycloalkyl. Among theseH, ethyl and cyclopropyl are presently most preferred.

The most preferred novel compounds used in accordance with the inventionare disclosed in Tables 2 through 9 with reference to Formulas 9 through16. The compounds specifically shown in Tables 2 through 9 arecarboxylic acids, but it should be understood that the use of thecorresponding C₁₋₃alkyl esters, methoxymethyl (OCH₂CH₃) esters and ofpharmaceutically acceptable salts of the acids shown in these tables isalso highly preferred.

It should also be apparent that the preferred compounds shown in Table 2with reference to the more specific Formula 9 are within the scope ofFormula 1.

Similarly, the preferred compounds shown in Table 3 with reference tothe more specific Formula 10 are within the scope of Formula 2;

-   -   the preferred compounds shown in Table 4 with reference to the        more specific Formula 11 are within the scope of Formula 3;    -   the preferred compounds shown in Table 5 with reference to the        more specific Formula 12 are within the scope of Formula 4;    -   the preferred compounds shown in Table 6 with reference to the        more specific Formula 13 are within the scope of Formula 5;    -   the preferred compounds shown in Table 7 with reference to the        more specific Formula 14 are within the scope of Formula 6;    -   the preferred compounds shown in Table 8 with reference to the        more specific Formula 15 are within the scope of Formula 7, and    -   the preferred compounds shown in Table 9 with reference to the        more 2 specific Formula 16 are within the scope of Formula 8.

TABLE 2 Com- pound Position of No. X Y Z R₂ n (CH₂)_(n)COOH 40 O H —C≡C—H 0 4 42 O H —C≡C— H 1 4 44 O H —C≡C— F 0 4 48 O cyclopropyl —C≡C— H 1 450 O cyclopropyl —C≡C— F 1 4 52 O cyclopropyl —C≡C— H 0 4 54 Ocyclopropyl —C≡C— F 0 4 58 O cyclopropyl —CO—O— H 1 4 60 O cyclopropyl—CO—O— H 1 3 66 CH₃N H —C≡C— H 0 4

TABLE 3 Compound No. R₅ X R₃ n 110 n-propyl (n-propyl)N H 0 112 benzylNH H 0 114 benzyl (n-benzyl)N H 0 108 n-propyl NH H 0 116 benzyl methylNH 0 77 benzyl O H 0 78 benzyl O H 1 70 methyl O H 1 69 methyl O H 0 73isopropyl O H 0 74 isopropyl O H 1 82 benzyl O methyl 1 81 benzyl Omethyl 0 89 (CH₃)₃C—CH_(2—) O methyl 0 90 (CH₃)₃C—CH_(2—) O methyl 1 94benzyl O ethyl 1 93 benzyl O ethyl 0 86 isopropyl O methyl 1 85isopropyl O methyl 0 105 ethyl O t-butyl 0 106 ethyl O t-butyl 1 98isopropyl O ethyl 1

TABLE 4 Compound No. R₂ 22 F 24 H

TABLE 5 Compound No. X₁ R₂ n 3 methyl,cyclopropyl-N H 0 8methyl,cyclopropyl-N H 1 13 methyl,cyclopropyl-N F 0 18methyl,cyclopropyl-N F 1 139 1-imidazolyl H 0 137 1-imidazolyl H 1 26methyl,isopropyl-N H 0

TABLE 6 Compound No. R₂ R₇ Y R₃ 143 H methyl t-butyl t-butyl 145 Fmethyl t-butyl t-butyl

TABLE 7 Compound No. X₂ R₃ n 119 1-imidazolyl methyl 0 121 1-imidazolylmethyl 1 127 1-imidazolyl iso-propyl 1 126 1-imidazolyl iso-propyl 0 134ethyl,cyclopropyl-N iso-propyl 0 130 ethyl,cyclopropyl-N methyl 0 131ethyl,cyclopropyl-N methyl 1 141 (1-methyl)cyclopropyl- iso- 1 oxypropyl

TABLE 8 Compound No. R R₂ n 62 H H 0 63 Me H 1

TABLE 9 Compound No. X₃ Y₁ R₃ Z R₂ n 28 O H methyl —C≡C— H 1 30 O Hmethyl —C≡C— F 0 5 CO H H —C≡C H 1 10 CO H H —C≡C— F 0 36 O cyclopropylmethyl —C≡C— H 1 38 O cyclopropyl methyl —C≡C— F 1 46 O H methyl —CO—O—H 1 20 CO H H —CO—O— H 1 32 O H methyl —C≡C— F 1 56 O ethyl methyl —C≡C—H 1 34 O cyclopropyl methyl —C≡C— H 0 15 CO H H —C≡C— F 1

The compounds used in accordance with the invention can be synthesizedby applying the general synthetic methodology described above, and bysuch modifications of the hereinafter described specific syntheticroutes which will become readily apparent to the practicing syntheticorganic chemist in light of this disclosure and in view of generalknowledge available in the art. The hereinafter disclosed specificreaction schemes are directed to the synthesis of exemplary andpreferred compounds used in accordance with the invention. Whereas eachof the specific and exemplary synthetic routes shown in these schemesmay describe specific compounds only within the scope of one or two ofthe general Formulas 1 through 8, the synthetic processes and methodsused therein are adaptable within the skill of the practicing organicchemist and can be used with such adaptation for the synthesis ofcompounds used in accordance with the invention which are notspecifically described herein as examples.

Reaction Scheme 1 discloses a presently preferred synthetic route tocertain intermediates or reagents having the general formulaX₄—A(R₂)—CH₂)_(n)—COOR₈, where the symbol A represents a di-, ortri-substituted phenyl moiety. These intermediates are utilized in thesynthesis of the novel compounds used in accordance with the invention.

Reaction Scheme 2 discloses presently preferred synthetic routes toobtain exemplary and preferred novel tetrahydronaphthalenone compoundswithin the scope of Formula 8 where the the symbol X₃ represents a C═Ogroup, Z represents an ethynyl moiety or a —COO— (ester) function, and Ais a substituted phenyl moiety.

Reaction Scheme 3 discloses presently preferred synthetic routes toobtain exemplary and preferred novel tetrahydronaphthalene compoundswithin the scope of Formula 4 where X₁ represents a dialkyl substitutednitrogen, Z is an ethynyl moiety and A is a substituted phenyl moiety.

Reaction Scheme 4 discloses presently preferred synthetic routes toobtain exemplary and preferred novel isoquinoline compounds within thescope of Formula 3 where the symbol Y represents hydrogen, Z is anethynyl moiety and A is a substituted phenyl moiety.

Reaction Scheme 5 discloses presently preferred synthetic routes toobtain exemplary and preferred novel chroman compounds within the scopeof Formula 8 where the symbol Y₁ represents hydrogen, Z is an ethynylmoiety or an ester (COO) function, and A is a substituted phenyl moiety.

Reaction Scheme 6 discloses presently preferred synthetic routes toobtain other exemplary and preferred novel chroman compounds within thescope of Formula 8 where the symbol Y₁ represents a cyclopropyl group, Zis an ethynyl moiety and A is a substituted phenyl moiety.

Reaction Scheme 7 discloses presently preferred synthetic routes toobtain exemplary and preferred novel chroman compounds within the scopeof Formula 1 where the symbol X represents oxygen (O), Y representshydrogen, Z is an ethynyl moiety and A is a substituted phenyl moiety.

Reaction Scheme 8 discloses presently preferred synthetic routes toobtain other exemplary and preferred novel chroman compounds within thescope of Formula 1 where the symbol X represents oxygen (O), Yrepresents a cyclopropyl group, Z is an ethynyl moiety and A is asubstituted phenyl moiety.

Reaction Scheme 9 discloses presently preferred synthetic routes toobtain exemplary and preferred novel tetrahydroquinoline compoundswithin the scope of Formula 1 where the symbol X represents an alkylsubstituted nitrogen (alkyl-N), Y represents hydrogen, Z is an ethynylmoiety and A is a substituted phenyl moiety.

Reaction Schemes 10 and 11 disclose presently preferred synthetic routesto obtain exemplary and preferred novel phenyl compounds within thescope of Formula 2 where the symbol X represents oxygen (O), R₅ is alkylor benzyl, Z is an ethynyl moiety and A is a substituted phenyl moiety.

Reaction Scheme 12 discloses presently preferred synthetic routes toobtain exemplary and preferred novel phenyl compounds within the scopeof Formula 2 where the symbol R₅—X represents an alkyl, dialkyl, benzylor dibenzyl substituted nitrogen, Z is an ethynyl moiety and A is asubstituted phenyl moiety.

Reaction Schemes 13 and 14 disclose presently preferred synthetic routesto obtain exemplary and preferred novel phenyl compounds within thescope of Formula 6 where the symbol X₂ represents a (1-imidazolyl)moiety, Z is an ethynyl moiety and A is a substituted phenyl moiety.

Reaction Scheme 15 disclose presently preferred synthetic routes toobtain exemplary and preferred novel phenyl compounds within the scopeof Formula 6 where X₂ represents an alkyl and cyclopropyl substitutednitrogen (X₂=(alkyl,cycloalkyl)N), Y represents hydrogen, Z is anethynyl moiety and A is a substituted phenyl moiety.

Reaction Scheme 16 discloses presently preferred synthetic routes toobtain exemplary and preferred novel tetrahydronaphthalene compoundswithin the scope of Formula 4 where the symbol X₁ represents a(1-imidazolyl) moiety, Y represents hydrogen, Z is an ethynyl moiety andA is a substituted phenyl moiety.

Reaction Scheme 17 discloses presently preferred synthetic routes toobtain exemplary and preferred novel phenyl compounds within the scopeof Formula 6 where the symbol X₂ represents a 1-methyl-cyclopropoxymoiety, Y represents hydrogen, Z is an ethynyl moiety and A is asubstituted phenyl moiety.

Reaction Scheme 18 discloses presently preferred synthetic routes toobtain exemplary and preferred novel phenyl compounds within the scopeof Formula 5 where the symbol X represents oxygen (O), Y represents atertiary-butyl group, Z is an ethynyl moiety and A is a substitutedphenyl moiety.

Certain known compounds which have been discovered in accordance withthe present invention to be useful as inhibitors of cytochrome P450RAIare shown by Formula A where R₈ generally represents H, alkyl of 1 to 6carbons, —CH₂O(C₁₋₆-alkyl), or a cation of a pharmaceutically acceptablebase, and where the other variables have the following specific values:

-   In Compound 201 X₅═O, X₆═CH, n=0, R₈═H or a cation of a    pharmaceutically acceptable base and R₁₀═CH₃.-   In Compound 202 X₅═S, X₆═CH, n=1, R₈═H or a cation of a    pharmaceutically acceptable base and R₁₀═H.-   In Compound 210 X₅═S, X₆═CH, n=2, R₈═H or a cation of a    pharmaceutically acceptable base and R₁₀═H.-   In Compound 215 X₅═S, X₆═CH, n=0, R₈═H or a cation of a    pharmaceutically acceptable base and R₁₀═H.-   In Compound 238 X₅═S, X₆═N, n=0, R₈═H or a cation of a    pharmaceutically acceptable base, R₁₀═H.

Compound 201 is described as compound 4 in U.S. Pat. No. 4,980,369incorporated herein by reference. Compounds 202, 210, and 215 aredescribed in U.S. Pat. No. 4,810,804 incorporated herein by reference.Compound 215 is example 12 of U.S. Pat. No. 4,810,804. Compound 238 isdescribed in U.S. Pat. No. 5,089,509 incorporated herein by reference(see claim 5 of U.S. Pat. No. 5,089,509).

Other known compounds which have been discovered in accordance with thepresent invention to be useful as inhibitors of cytochrome P450RAI areshown by Formula B where R₈ generally represents H, alkyl of 1 to 6carbons, —CH₂O(C₁₋₆-alkyl), or a cation of a pharmaceutically acceptablebase.

Specifically in Compound 240 R₈ is H or a cation of a pharmaceuticallyacceptable base. Compound 240 is described and can be made in accordancewith the teachings of U.S. Pat. Nos. 5,089,509, 5,602,130 or 5,348,972all of which are incorporated herein by reference.

Still other known compounds which have been discovered in accordancewith the present invention to be useful as inhibitors of cytochromeP450RAI are shown by Formula C where R₈ generally represents H, alkyl of1 to 6 carbons, —CH₂O(C₁₋₆-alkyl), or a cation of a pharmaceuticallyacceptable base, and where the other variables have the followingspecific values:

-   In Compound 203 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₀═CH₃, R₁₁═Cl, R₁₂═F and X₆═CH.-   In Compound 204 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₀═CH₃, R₁₁=cyclopropyl, R₁₂═F and X₆═CH.-   In Compound 205 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₀═CH₃, R₁₁═CF₃, R₁₂═F and X₆═CH.-   In Compound 206 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₀═CH₃CH₂, R₁₁═Br, R₁₂═F and X₆═CH.-   In Compound 220 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₀═CH₃, R₁₁═CH₃, R₁₂═F and X₆═CH.-   In Compound 221 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₀═CH₃, R₁₁═Cl, R₁₂═F and X₆═N.-   In Compound 224 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₀═CH₃, R₁₁=phenyl, R₁₂═F and X₆═CH.-   In Compound 225 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₀═H, R₁₁═Br, R₁₂═F and X₆═CH.-   In Compound 226 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₀═CH₃, R₁₁═OCH₃, R₁₂═F and X₆═CH.-   In Compound 227 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₀═CH₃, R₁₁═CH₃, R₁₂═H and X₆═CH.-   In Compound 228 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₀═CH₃, R₁₁═H, R₂═F and X₆═CH.-   In Compound 247 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₀═CH₃, R₁₁═Br, R₁₂═F and X₆═CH.-   In Compound 248 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₀═CH₃, R₁₁═CF₃CF₂, R₁₂═F and X₆═CH.-   In Compound 249 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₀═CH₃, R₁₁═CH₃, CH₂, R₁₂═F and X₆═CH.-   In Compound 250 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₀=CH₃, R₁₁=iso-propyl, R₁₂═F and X₆═CH.-   In Compound 251 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₀═CH₃, R₁₁=(1-methyl)cyclopropyl, R₁₂═F and X₆═CH.-   In Compound 252 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₀═CH₃, R₁₁=tertiary-butyl, R₁₂═F and X₆═CH.-   In Compound 253 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₀═CH₃, R₁₁=(2,2-difluoro)cyclopropyl, R₁₂═F and X₆═CH.-   In Compound 254 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₀═CH₃, R₁₁=(cyclopropyl)methyl, R₁₂═F and X₆═CH.

Compounds 203-206, 220, 221, 224-228 and 247-254 are described and canbe made in accordance with the teachings of U.S. Pat. No. 5,675,024which is incorporated herein by reference. (Compound 205 is compound orexample 14, Compound 225 is compound or example 10, and Compound 228 iscompound or example 32 in U.S. Pat. No. 5,675,024. Compound 220 is alsodescribed in U.S. Pat. No. 5,965,606, incorporated herein by reference.

Still other known compounds which have been discovered in accordancewith the present invention to be useful as inhibitors of cytochromeP450RAI are shown by Formula D where R₈ generally represents H, alkyl of1 to 6 carbons, —CH₂O(C₁₋₆-alkyl), or a cation of a pharmaceuticallyacceptable base, and where the other variables have the followingspecific values:

-   In Compound 207 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₂═H, the two R₁₃ groups jointly represent an oxo (═O)    function and R₁₄═CH₃.-   In Compound 208 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₂═H, R₁₃═H and R₁₄═CH₃.-   In Compound 216 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₂═H, R₁₃═CH₃ and R₁₄═CH₃.-   In Compound 218 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₂═H, R₁₃═CH₃ and R₁₄═H.-   In Compound 230 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₂═F, R₁₃═CH₃ and R₁₄═CH₃.-   In Compound 232 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₂═H, one of the R₁₃ groups is H, the other is OH and    R₁₄═CH₃.

Compound 207 is described (as compound 7) in U.S. Pat. No. 5,489,584incorporated herein by reference. Compound 232 is described (as compound42) in U.S. Pat. No. 5,654,469 incorporated herein by reference.Compounds 208, 216 and 218 are described in the publication byChandraratna el al. J. Eur. J. Med. Chem., Suppl. to Vol. 30, 1995, 506s-517s. Compound 230 can also be made in accordance with the teachings ofthe publication by Chandraratna el al. J. Eur. J. Med. Chem., Suppl toVol. 30, 1995, 506s-517s, incorporated herein by reference, or by suchmodification of the synthetic procedures of this reference which will bereadily apparent to those skilled in the art.

Still further known compounds which have been discovered in accordancewith the present invention to be useful as inhibitors of cytochromeP450RAI are shown by Formula E where R₈ generally represents H, alkyl of1 to 6 carbons, —CH₂O(C₁₋₆-alkyl), or a cation of a pharmaceuticallyacceptable base, and where the other variables have the followingspecific values:

-   In Compound 209 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₂═H, R₁₅=tertiary-butyl, R₁₆═OH and R₁₇═Cl.-   In Compound 211 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₂═H, R₁₅=tertiary-butyl, R₁₆═OCH₃ and R₁₇=tertiary-butyl.-   In Compound 214 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₂═H, R₁₅=1-adamantyl, R₁₆═OCH₃ and R₁₇═H.-   In Compound 235 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₂═H, R₁₅=tertiary-butyl, R₁₆═OH and R₁₇=tertiary-butyl.-   In Compound 236 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₂═F, R₁₅=tertiary-butyl, R₁₆═OH and R₁₇═H.

Compound 211 is described and can be made in accordance with theteachings of U.S. Pat. No. 5,202,471, and Compound 235 is described andcan be made in accordance with the teachings of U.S. Pat. No. 5,498,795.The specification of U.S. Pat. Nos. 5,202,471 and 5,498,795 areincorporated herein by reference. Compounds 209, 214 and 236 can also bemade in accordance with the teachings of U.S. Pat. Nos. 5,202,471 and5,498,795 with such modifications of the synthetic procedures which willbe readily apparent to those skilled in the art.

Still more known compounds which have been discovered in accordance withthe present invention to be useful as inhibitors of cytochrome P450RAIare shown by Formula F where R₈ generally represents H, alkyl of 1 to 6carbons, —CH₂O(C₁₋₆-alkyl), or a cation of a pharmaceutically acceptablebase, and where the other variables have the following specific values:

-   In Compound 222 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₂═F, R₁₅=tertiary-butyl, R₁₆═CH₃CH₂O and R₁₇═l.-   In Compound 223 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₂═F, R₁₅=tertiary-butyl, R₁₆═CH₃CH₂0 and R₁₇═Br.

Compounds 222 and 223 are described and can be made in accordance withthe teachings of U.S. Pat. Nos. 5,663,357 and 5,917,048, thespecifications of which are incorporated herein by reference.

Yet more known compounds which have been discovered in accordance withthe present invention to be useful as inhibitors of cytochrome P450RAIare shown by Formula G where R₈ generally represents H, alkyl of 1 to 6carbons, —CH₂O(C₁₋₆-alkyl), or a cation of a pharmaceutically acceptablebase, and where the other variables have the following specific values:

-   In Compound 212 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₂═H, X₆═CH and X₇═(CH₃)₂C.-   In Compound 217 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₂═H, X₆═CH and X₇═CH₂.-   In Compound 219 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₂═H, X₆═CH and X₇═S.-   In Compound 229 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₂═F, X₆═CH and X₇═CH₂.-   In Compound 244 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₂═H, X₆═N and X₇═CH₂.

Compounds 217 is described (as example or compound 4) and can be made inaccordance with the teachings of U.S. Pat. No. 4,739,098 thespecification of which is incorporated herein by reference. Compounds219 is described (as compound 2) and can be made in accordance with theteachings of U.S. Pat. No. 5,688,957, the specification of which isincorporated herein by reference. Compound 212 and Compound 229 can bemade in accordance with the teachings of U.S. Pat. No. 4,739,098 and incase of Compound 212 also in accordance with U.S. Pat. No. 5,426,118,with such modifications of the synthetic procedures which will bereadily apparent to those skilled in the art. The specification of U.S.Pat. No. 5,426,118 is incorporated herein by reference. Compound 244 isdescribed (as compound or example 7) and can be made in accordance withthe teachings of U.S. Pat. No. 4,923,884, the specification of which isincorporated herein by reference.

Still more known compounds which have been discovered in accordance withthe present invention to be useful as inhibitors of cytochrome P450RAIare shown by Formula H where R₈ generally represents H, alkyl of 1 to 6carbons, —CH₂O(C₁₋₆-alkyl), or a cation of a pharmaceutically acceptablebase.

Specifically in Compound 245 R₈ is H or a cation of a pharmaceuticallyacceptable base.

Compounds 245 is described and can be made in accordance with theteachings of U.S. Pat. No. 4,923,884.

Further known compounds which have been discovered in accordance withthe present invention to be useful as inhibitors of cytochrome P450RAIare shown by Formula 1 where R₈ generally represents H, alkyl of 1 to 6carbons, —CH₂O(C₁₋₆-alkyl), or a cation of a pharmaceutically acceptablebase.

Specifically in Compound 242 R₈ is H or a cation of a pharmaceuticallyacceptable base.

Compound 242 is described in the publication by Bernard et al. Biochem.Biophys. Res. Commun., 1992, Vol. 186, 977-983, incorporated herein byreference.

Still more known compounds which have been discovered in accordance withthe present invention to be useful as inhibitors of cytochrome P450RAIare shown by Formula J where R₈ generally represents H, alkyl of 1 to 6carbons, —CH₂O(C₁₋₆-alkyl), or a cation of a pharmaceutically acceptablebase, and where the other variables have the following specific values:

-   In Compound 237 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₂═F, R₁₈═H and R₁₉═H.-   In Compound 246 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₂═H, R₁₈═OH and R₁₉═F.

Compounds 237 and 246 are described and can be made in accordance withthe teachings of U.S. Pat. Nos. 5,675,024 and 5,856,490. Compound 237 iscompound or example 2 of U.S. Pat. No. 5,675,024. The specification ofU.S. Pat. No. 5,856,490 is incorporated herein by reference.

Additional known compounds which have been discovered in accordance withthe present invention to be useful as inhibitors of cytochrome P450RAIare shown by Formula K where R₈ generally represents H, alkyl of 1 to 6carbons, —CH₂O(C₁₋₆-alkyl), or a cation of a pharmaceutically acceptablebase.

Specifically in Compound 231 R₈ is H or a cation of a pharmaceuticallyacceptable base.

Compound 231 is described (as compound 2) in U.S. Pat. No. 5,006,550,the specification of which is incorporated herein by reference.

Still more known compounds which have been discovered in accordance withthe present invention to be useful as inhibitors of cytochrome P450RAIare shown by Formula L where R₈ generally represents H, alkyl of 1 to 6carbons, —CH₂O(C₁₋₆-alkyl), or a cation of a pharmaceutically acceptablebase.

Specifically in Compound 243 R₈ is H or a cation of a pharmaceuticallyacceptable base.

Compound 243 is described (as example or compound 7) in U.S. Pat. No.5,130,335, the specification of which is incorporated herein byreference.

Still more known compounds which have been discovered in accordance withthe present invention to be useful as inhibitors of cytochrome P450RAIare shown by Formula M where R₈ generally represents H, alkyl of 1 to 6carbons, —CH₂O(C₁₋₆-alkyl), or a cation of a pharmaceutically acceptablebase, and where the other variables have the following specific values:

-   In Compound 233 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₅=1-adamantyl and R₁₆═OH.-   In Compound 234 R₈ is H or a cation of a pharmaceutically acceptable    base, R₁₅=1-adamantyl and R₁₆═OCH₃.

Compounds 233 and 234 are described in the publication by Shroot et al.J. M. EP 199636 (1986) incorporated herein by reference.

Further known compounds which have been discovered in accordance withthe present invention to be useful as inhibitors of cytochrome P450RAIare shown by Formula N where R₈ generally represents H, alkyl of 1 to 6carbons, —CH₂O(C₁₋₆-alkyl), or a cation of a pharmaceutically acceptablebase.

Specifically in Compound 241 R₈ is H or a cation of a pharmaceuticallyacceptable base.

Compound 241 is described in the publication by Dawson et al. J. Med.Chem., 1983, Vol. 26, 1653-1656. incorporated herein by reference.

Still further compounds which have been discovered in accordance withthe present invention to be useful as inhibitors of cytochrome P450RAIare shown by Formula O where R₈ generally represents H, alkyl of 1 to 6carbons, —CH₂O(C₁₋₆-alkyl), or a cation of a pharmaceutically acceptablebase.

Specifically in Compound 247 R₈ is H or a cation of a pharmaceuticallyacceptable base. Compound 247 is described in the publication by Winumet al. II Farmaco, 1997, Vol. 52, 1, p39-42, incorporated herein byreference.

The P450RAI inhibition data of this compound are provided in Table 1A,and the cutaneous toxicity score (blackjack score) of the compound inthe topical skin irritation tests provided above, are disclosed in Table1B.

SPECIFIC EXAMPLES OF NEW COMPOUNDS

4-Hydroxy phenyl acetic acid-t-butyl ester (Reagent E)

A stirred suspension of 4-hydroxy-phenyl acetic acid (0.1 52 g, 1 mmol)in anhydrous toluene (5 mL) was heated at 80° C. and N,N-dimethylformamide-di-t-butyl acetal (1 mL, 4.17 mmol) was added when thesolution became homogenous. After 0.5 h, the reaction mixture was cooledto ambient temperature and the volatiles were distilled off in vacuo.The residue was diluted with water and extracted with diethyl ether(×2). The combined organic extract was dried over anhydrous sodiumsulfate, filtered and evaporated in vacuo to afford an oil which wassubjected to flash column chromatography over silica gel (230-400 mesh)using 16% ethyl acetate in hexane as the eluent to afford the titlecompound as a solid (0.11 g, 56%).

¹H-NMR (300 MHz, CDCl₃):δ 1.44(s, 9H), 3.45(s, 2H), 6.55(s, 1H), 6.69(d,J=8.8 Hz, 2H), 7.06(d, J=8.5 Hz, 2H).

3-Hydroxy phenyl acetic acid-t-butyl ester (Reagent F)

A stirred suspension of 3-hydroxy-phenyl acetic acid (1.52 g, 10 mmol)in anhydrous toluene (20 mL) was heated at 80° C. and N,N-dimethylformamide-di-t-butyl acetal (9.6 mL, 40 mmol) was added when thesolution became homogenous. After 0.5 h, the reaction mixture was cooledto ambient temperature and the volatiles were distilled off in vacuo. Thresidue was diluted with water and extracted with diethyl ether (×2).The combined organic extract was dried over anhydrous sodium sulfate,filtered and evaporated in vacuo to afford an oil which was subjected toflash column chromatography over silica gel (230-400 mesh) using 16%ethyl acetate in hexane as the eluent to afford the title compound as asolid (1.17 g, 56%).

¹H-NMR (300 MHz, CDCl₃):δ 1.47(s, 9H), 3.49(s, 2H), 6.30(s, 1H),6.70-6.79 (m, 2H), 6.81(d, J=7.6 Hz, 1H), 7.16(t, J=7.7 Hz, 1H).

Methyl-2-fluoro-4-iodo benzoate (Reagent G)

A solution of 2-fluoro-4-iodo toluene (5 g, 26.6 mmol) in pyridine (2mL) and water (20 mL) was treated with potassium permanganate (16.6 g,105 mmol) and heated at 150° C. overnight. The reaction mixture was thencooled to room temperature and filtered and the filtrate was extractedwith hexane. The aqueous phase was acidified with 10% hydrochloric acidand extracted with ethyl acetate. The organic phase was dried overanhydrous sodium sulfate, filtered and evaporated in vacuo. The residuewas dissolved in 20 mL of methanol, treated with concentrated sulfuricacid (1 mL) and refluxed overnight. The volatiles were distilled off invacuo and the residue was dissolved in diethyl ether, washed with brine,dried over anhydrous sodium sulfate, filtered and evaporated in vacuo toan oil. Flash column chromatography over silica gel (230-400 mesh) using10% ethyl acetate in hexane as the eluent afforded the title compound asan oil (0.26 g, 5%).

¹H NMR (300 MHz, CDCl₃): δ 7.60 (m, 4H), 3.93 (s, 3H).

Ethyl-2-fluoro-4-hydroxy benzoate (Reagent I)

A solution of 2-fluoro-4-hydroxy benzoic acid (Intermediate 4, 3 g, 19.2mmol) in ethanol (65 mL) and benzene (90 mL) was treated withconcentrated sulfuric acid (1.5 mL) and heated at reflux overnight usinga Dean-Stark water trap. The volatiles were distilled off in vacuo andthe residue was diluted with water and diethyl ether. The phases wereseparated and the organic phase was washed with saturated aqueous sodiumbicarbonate (×1), water (×1) and brine (×1), dried over anhydrousmagnesium sulfate, filtered and evaporated in vacuo to afford the titlecompound as a solid (3.07 g, 86%).

¹H-NMR (300 MHz, CD₃COCD₃): δ 1.34 (t, J=7.1 Hz, 3H), 4.32 (q, J=7.1 Hz,2H), 6.66(dd, J=2.6, 10.9 Hz, 1H), 6.76 (dd, J=2.3, 8.5 Hz, 1H), 7.83(d,J=8.4 Hz, 1H), 9.91 (s, 1H).

Ethyl-2-fluoro-4-trifluoromethylsulfonyloxy-benzoate (Intermediate 6)

A stirred, cooled (ice bath) solution ofethyl-2-fluoro-4-hydroxy-benzoate (Intermediate 5, 0.36 g, 2 mmol) and2,6-di-tert-butyl-4-methyl-pyridine (0.8 g, 8 mmol) in 8 mL ofdichloromethane was treated with trifluoromethanesulfonic anhydride (0.1g, 4 mmol). The reaction mixture was allowed to warm to ambienttemperature and stirred overnight. The reaction mixture was subjected toflash column chromatography over silica gel (230-400 mesh) using 5-10%ethyl acetate in hexane as the eluent to afford the title compound (0.53g, 85%).

¹H-NMR (300 MHz, CDCl₃): δ 1.41 (t, J=7.3 Hz, 4H), 4.42 (q, J=7.1 Hz,2H), 7.12-7.20(m, 2H), 8.08(t, J=8.3 Hz, 1H).

Ethyl-2-fluoro-4-trimethylsilanylethynyl-benzoate (Intermediate 7)

A solution of ethyl-2-fluoro-4-trifluoromethylsulfonyloxy-benzoate(Intermediate 6, 1.82 g, 6 mmol) in triethyl amine (12 mL) and anhydroustetrahydrofuran (30 mL) was treated with copper(I)iodide (0.12 g, 0.6mmol) and sparged with argon.Dichlorobis(triphenylphosphine)palladium(II) (0.43 g, 0.6 mmol) wasadded followed by (trimethylsilyl)acetylene (3.6 mL, 24 mmol) and theresulting reaction mixture was heated at 70° C. overnight. It was thencooled to ambient temperature, diluted with diethyl ether and filteredover a bed of celite. The filtrate was evaporated in vacuo to an oilwhich was subjected to flash column chromatography over silica gel(230-400 mesh) using 5% ethyl acetate in hexane as the eluent to affordthe title compound as an orange oil (1.5 g, quantitative).

¹H-NMR (300 MHz, CDCl₃):δ 0.011 (s, 9H), 1.13(t, J=7.1 Hz, 4H), 4.13 (q,J=7.1 Hz, 2H), 6.93-7.02(m, 2H), 7.07 (s, 1H), 7.61(t, J=7.9 Hz, 1H).

Ethyl-4-ethynyl-2-fluoro benzoate (Reagent D)

A solution of ethyl-2-fluoro-4-trimethylsilanylethynyl-benzoate(Intermediate 7, 1.5 g, 6 mmol) in ethanol (16 mL) was treated withpotassium carbonate (1.485 g, 10.74 mmol) and stirred overnight at roomtemperature. The reaction mixture was then diluted with water andextracted with diethyl ether (×2). The combined organic phase was driedover anhydrous magnesium sulfate, filtered and evaporated in vacuo toafford an orange oil. Flash column chromatography over silica gel(230-400 mesh) using 5% ethyl acetate in hexane as the eluent affordedthe title compound (1 g, 86%).

¹H-NMR (300 MHz, CDCl₃):δ 1.39 (t, J=7.1 Hz, 4H), 3.26 (s, 1H), 4.39 (q,J=7.1 Hz, 2H), 7.22-7.33 (m, 2H), 7.88(t, J=7.7 Hz, 1H).

Methyl-4-iodo-phenyl acetate (Reagent B)

A solution of 4-iodo phenyl acetic acid (5 g, 19 mmol) in methanol wastreated with concentrated sulfuric acid (0.5 mL) and refluxed overnight.The volatiles were distilled off in vacuo and the residue was dissolvedin ethyl acetate, washed with brine, dried over anhydrous sodiumsulfate, filtered and evaporated in vacuo to an oil which was subjectedto flash column chromatography over silica gel (230-400 mesh) using 5%ethyl acetate in hexane as the eluent to afford the title compound as aclear oil (5 g, 95%).

¹H NMR (300 MHz, CDCl₃): δ 7.63 (d, 2H, J=8.5 Hz), 7.01 (d, 2H, J=8.0Hz), 3.67 (s, 4H), 3.55 (s, 2H).

2-Fluoro-4-iodo-phenyl acetonitrile (Intermediate 2)

A solution of 2-fluoro-4-iodo-benzyl bromide (Intermediate 1, 2.56 g,8.15 mmol) in ethanol (55 mL and water (10 mL) was treated with sodiumcyanide (2.15 g, 43.86 mmol) and refluxed for 0.5 h. The volatiles weredistilled off in vacuo and the residue was diluted with water andextracted with diethyl ether (×2). The combined organic extract waswashed with water (×1) and brine (×1), dried over anhydrous magnesiumsulfate, filtered and evaporated in vacuo to afford the title compoundas a pale yellow solid (2.05 g, 96%).

¹H-NMR (300 MHz, CDC₃): δ 3.71(s, 4H), 7.16(t, J=8.2 Hz, 1H), 7.45(dd,J=1.7, 9.1 Hz, 1H), 7.51(dd, J=1.5, 8.2 Hz, 1H).

2-Fluoro-4-iodo-phenyl acetic acid (Intermediate 3)

A solution of 2-fluoro-4-iodo-phenyl acetonitrile (Intermediate 2, 2.05g, 7.83 mmol) in ethanol (50 mL and water (15 mL) was treated withpotassium hydroxide (3.4 g, 60.7 mmol) and refluxed for 4 h. Thevolatiles were distilled off in vacuo and the residue was diluted withwater and poured into cold, dilute hydrochloric acid and theprecipitated solid was filtered. The solid was dissolved in diethylether, and the organic solution was dried over anhydrous magnesiumsulfate, filtered and evaporated in vacuo to afford the title compound apale yellow solid (1.75 g, 79%).

¹H-NMR (300 MHz, CDCl₃):δ 3.64 (s, 2H), 6.98(t, J=7.9 Hz, 1H), 7.25-7.46(m, 2H), 9.60-10.40(br s, 1H).

Ethyl-2-fluoro-4-iodo-phenyl acetate (Reagent C)

A solution of 2-fluoro-iodo-phenyl acetic acid (Intermediate 3, 1.75 g,6.22 mmol) in ethanol (50 mL) and benzene (100 mL) was treated withconcentrated sulfuric acid (1.4 mL) and heated at reflux overnight usinga Dean-Stark water trap. The volatiles were distilled off in vacuo andthe residue was diluted with water and diethyl ether. The phases wereseparated and the organic phase was washed with saturated aqueous sodiumbicarbonate (×1), water (×1) and brine (×1), dried over anhydrousmagnesium sulfate, filtered and evaporated in vacuo to afford an oilwhich was subjected to flash column chromatography over silica gel(230-400 mesh) using 5%-10% ethyl acetate in hexane as the eluent toafford the title compound as a pale yellow solid (1.4 g, 73%).

¹H-NMR (300 MHz, CDCl₃): δ 1.25 (t, J=7.1 Hz, 4H), 3.60 (s, 2H), 4.16(q, J=7.1 Hz, 2H), 6.99(t, J=8.0 Hz, 1H), 7.39-7.44(m, 2H).

Methyl-2-fluoro-4-iodo-phenyl acetate (Reagent H)

A solution of 2-fluoro-4-iodo-phenyl acetonitrile (Intermediate 2, 3 g,11.45 mmol) in methanol (50 mL) and benzene (50 mL) was treated withp-toluene sulfonic acid (2.5 g, 13.15 mmol) and heated at refluxovernight using a Dean-Stark water trap. The volatiles were distilledoff in vacuo and the residue was diluted with water and diethyl ether.The phases were separated and the organic phase was washed withsaturated aqueous sodium bicarbonate (×1), water (×1) and brine (×1),dried over anhydrous magnesium sulfate, filtered and evaporated in vacuoto afford an oil which was subjected to flash column chromatography oversilica gel (230-400 mesh) using 6% ethyl acetate in hexane as the eluentto afford the title compound as a colorless oil (2.7 g, 80%).

¹H-NMR (300 MHz, CDCl₃):δ 3.62 (s, 2H), 3.70 (s, 4H), 6.99(t, J=7.9 Hz,1H), 7.39-7.45(m, 2H).

General Procedure A: 7-Methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalene (Intermediate 8)

A stirred, cooled (−40° C.) solution of titanium tetrachloride inanhydrous dichloromethane (1M, 20 mL) under argon, was treated with asolution of dimethyl zinc (2M, 40 mL) in toluene. After 0.5 h, asolution of 7-methoxy-1-tetralone (1.76 g, 10 mmol) in anhydrousdichloromethane (5mL) was cannulated into the reaction mixture and theresulting solution was allowed to warm to ambient temperature andstirred overnight. The reaction mixture was then cooled to −40° C. andcautiously quenched with methanol (11 mL). It was diluted withdichloromethane and saturated aqueous ammonium chloride solution. Thephases were separated and the aqueous phase was extracted withdichloromethane (×2 mL). The combined organic phase was dried overanhydrous sodium sulfate, filtered and evaporated in vacuo to the titlecompound (1.75 g, 92%) as an oil.

¹H-NMR (300 MHz, CDCl₃):δ 1.33(s, 6H), 1.67-1.71(m, 2H), 1.79-1.90(m,2H), 2.75(t, J=6.2 Hz, 2H), 3.83(s, 4H), 6.72(dd, J=2.6, 8.3 Hz, 1H),6.93(d, J=2.6 Hz, 1H), 7.02(d, J=8.3 Hz, 1H).

General Procedure B:6-Methoxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-1-one (Intermediate9)

A solution of 7-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalene(Intermediate 8, 1.65 g, 8.7 mmol) in 7.5 mL of glacial acetic acid wascooled to 0° C. and treated with a solution of chromium trioxide (2 g,20 mmol) in 8mL of acetic acid and 7 mL of water. The reaction mixturewas then allowed to warm to ambient temperature and stirred overnight.It was diluted with water and extracted with diethyl ether (×2). Thecombined organic phase was washed with water (×1), saturated aqueoussodium bicarbonate (×1) and brine (×1), dried over anhydrous magnesiumsulfate, filtered and evaporated in vacuo to afford the title compound(1.64 g, 93%) as a yellow oil.

¹H-NMR (300 MHz, CDCl₃):δ 1.34(s, 6H), 1.96(t, J=7.1 Hz, 2H), 2.64(t,J=7.1 Hz, 2H), 3.83(s, 4H), 6.77(dd, J=2.6, 8.7 Hz, 1H), 6.83(d, J=2.5Hz, 1H), 7.98(d, J=8.7 Hz, 1H).

6-Hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-1-one (Intermediate10)

A stirred, cooled (−78° C.) solution of6-methoxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-1-one Intermediate9, 0.8, 3 mmol) under argon was treated with a 1M solution of borontribromide (10 mL). The reaction mixture was allowed to warm to ambienttemperature and stirred overnight. The reaction mixture was cooled to−78° C., quenched and diluted with saturated aqueous sodium bicarbonatesolution and the aqueous phase was extracted with dichloromethane (×2).The combined organic phase was dried over anhydrous sodium sulfate,filtered and evaporated in vacuo to an oil. Flash column chromatographyover silica gel (230-400 mesh) using 30% ethyl acetate in hexane as theeluent afforded the title compound (0.3 g, 52%) as a yellow viscous oil.

¹H-NMR (300 MHz, CDCl₃):δ 1.33(s, 6H), 1.97(t, J=6.8 Hz, 2H), 2.71(t,J=6.7 Hz, 2H), 6.81(dd, J=2.3, 8.5 Hz, 1H), 6.94(d, J=2.3 Hz, 1H),7.98(d, J=8.7 Hz, 1H), 9.35(s, 1H).

General Procedure C: 4,4-Dimethyl-6-trifluoromethylsulfonyloxy-1,2,34-tetrahydronaphthalene-1-one (Intermediate 11)

A stirred, cooled (0° C.) solution of6-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-1-one (Intermediate10, 0.3 g, 1.6 mmol) in anhydrous dichloromethane (10 mL) was treatedwith 4-(dimethylamino)pyridine (0.36 g, 3.27 mmol) followed by2-[N,N′-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine (0.79 g, 2mmol). After stirring at ambient temperature for 0.75 h, the reactionmixture was diluted with dichloromethane and washed with water (×1). Theorganic phase was dried over anhydrous sodium sulfate, filtered andevaporated in vacuo to an oil. Flash column chromatography over silicagel (230-400 mesh) using 8-10% ethyl acetate in hexane as the eluentafforded the title compound (0.462 g, 90%) as an off-white solid.

¹H-NMR (300 MHz, CDCl₃): δ 1.36(s, 6H), 2.01(t, J=6.8 Hz, 2H), 2.70(t,J=6.7 Hz, 2H), 7.15(dd, J=2.5, 8.7 Hz, 1H), 7.28(d, J=2.4 Hz, 1H),8.06(d, J=8.7 Hz, 1H).

General Procedure D: 4,4-Dimethyl-6-trimethylsilanyl-ethynyl-1,2,34-tetrahydronaphthalene-1-one (Intermediate 12)

A solution of4,4-dimethyl-6-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydronaphthalene-1-one(Intermediate 11, 0.46 g, 1.43 mmol) in triethyl amine (3 mL) andanhydrous tetrahydrofuran (8 mL) was treated with copper(I)iodide (0.1g, 0.53 mmol) and sparged with argon for 5 minutes. Trimethylsilylacetylene (0.85 mL, 6 mmol) was then added followed bydichlorobis(triphenylphosphine)palladium(II) (0.25 g, 0.36 mmol). Theresulting reaction mixture was heated at 70° C. for 17 h. It was thencooled to ambient temperature, diluted with diethyl ether and filteredover a bed of celite. The filtrate was evaporated vacuo to an oil whichwas subjected to flash column chromatography over silica gel (230-400mesh) using 5% ethyl acetate in hexane as the eluent to afford the titlecompound (0.28 g, 72%).

¹H-NMR (300 MHz, CDCl₃): δ 0.26(s, 9H), 1.36(s, 6H), 1.99(t, J=6.8 Hz,2H), 2.69(t, J=6.7 Hz, 2H), 7.35(dd, J=1.7, 8.2 Hz, 1H), 7.49(unresolved d, 1H), 7.93(d, J=8.1 Hz, 1H).

General Procedure E:6-Ethynyl-4,4-dimethyl-1,2,3,4-tetrahydronphthalene-1-one (Intermediate13)

A solution of4,4-dimethyl-6-trimethylsilanylethynyl-1,2,3,4-tetrahydronaphthalene-1-one(Intermediate 12, 0.28 g, 1.03 mmol) in methanol (10 mL) was treatedwith potassium carbonate (0.74 g, 5.35 mmol) and stirred at ambienttemperature for 4 h. The volatiles were distilled off in vacuo and theresidue was diluted with water and extracted with diethyl ether (×2).The combined organic extract was dried over anhydrous magnesium sulfate,filtered and evaporated in vacuo to afford the title compound (0.19 g,89%) as an oil that solidified on standing.

¹H-NMR (300 MHz, CDCl3):δ 1.33(s, 6H), 1.96(t, J=6.8 Hz, 2H), 2.67(t,J=6.8 Hz, 2H), 3.25(S, 1H), 7.33(dd, J=1.5, 8.1 Hz, 1H), 7.49 (d,J=1.5Hz, 1H), 7.13(d, J=8.1 Hz, 1H).

General Procedure F:4-(8,8-Dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl)-benzoicacid ethyl ester (Intermediate 14)

A solution of 6-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-1-one(Intermediate 13, 0.23 g, 1.1 mmol) and ethyl-4-iodo benzoate (ReagentA, 0.36 g, 1.3 mmol) in triethyl amine (7 mL) and anhydroustetrahydrofuran (3 mL) was treated with copper(I)iodide (0.114 g, 0.6mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)palladium(II) (0.23 g, 0.33 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. It was diluted with diethyl ether and filtered over a bedof celite. The filtrate was evaporated in vacuo to a brown oil that wassubjected to flash column chromatography over silica gel (230-400 mesh)using 6-7% ethyl acetate in hexane as the eluent to afford the titlecompound (0.29 g, 72%) as a pale brown solid.

¹H-NMR (300 MHz, CDCl₃): δ 1.3(t, J=7.1 Hz, 4H), 1.37(s, 6H), 1.80 (t,J=6.8 Hz, 2H), 2.69(t, J=6.8 Hz, 2H), 4.35(q, J=7.1 Hz, 2H), 7.40(dd,J=1.5, 8.2 Hz, 1H), 7.51 (d, J=1.6 Hz, 1H), 7.57 (d, J=8.3 Hz, 2H),7.96(d,J=8.2 Hz, 1H), 7.99(d, J=8.5 Hz, 2H).

General Procedure G4-(5-Cyclopropylamino-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2yl-ethynyl)-benzoicacid ethyl (Compound 1,General Formula 4)

A solution of4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)-benzoicacid ethyl ester (Intermediate 14, 0.14 g, 0.4 mmol) in 3 mL ofdichloromethane and 2 mL of acetonitrile was treated with cyclopropylamine(1 mL, 14.45 mmol). After 5 minutes, acetic acid (1 mL) was addedfollowed by sodium cyanoborohydride (0.13 g, 2 mmol). The reaction wasstirred overnight at ambient temperature. It was then diluted with waterand saturated aqueous sodium carbonate solution and extracted withdichloromethane (×2). The combined organic extract was dried overanhydrous sodium sulfate, filtered and evaporated in vacuo to an oil.Flash column chromatography over silica gel (230-400 mesh) using 20%ethyl acetate in hexane as the eluent afforded the title compound (0.1g, 62%) as a pale yellow solid.

¹H-NMR (300 MHz, CDCl₃): δ 0.30-0.60(m, 4H), 1.28(s, 4H), 1.35 (s, 4 H),1.30(t, J=7.1 Hz, 4H), 1.55-1.61(m, 1H), 1.83-2.05(m, 4H), 2.25(quintet, J=3.0 Hz, 1H), 3.80 (t, J=4.9 Hz, 1H), 4.39(q, J=7.1 Hz, 2H),7.27-7.36(m, 2H), 7.52 (s, 1H), 7.55(d, J=8.3 Hz, 2H), 8.03(d, J=8.5 Hz,2H).

General Procedure H4-[(5-Cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl]-benzoicacid ethyl ester (Compound 2, General Formula 4)

A solution of4-(5-cyclopropylamino-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)-benzoicacid ethyl ester (Compound 1, 0.64 g, 0.16 mmol) in acetone (2 mL) wastreated with potassium carbonate (0.6 g, 4.34 mmol) and methyl iodide (1mL, 16 mmol) and stirred overnight at ambient temperature. The volatileswere distilled off in vacuo and the residue was diluted with water andextracted with dichloromethane (×2). The combined organic extract wasdried over anhydrous sodium sulfate, filtered and evaporated in vacuo toafford the title compound (0.065 g, 99%).

¹H-NMR (300 MHz, CDCl₃): δ 0.28-0.49 (m, 4H), 1.21(s, 4H), 1.26 (s, 4H), 1.33 (t, J=7.1 Hz, 4H), 1.58-1.73 (m, 2H), 1.83-1.89 (m, 2H),2.02-2.08 (m, 1H), 2.06 (s, 4H), 3.88 (t, J=8.1 Hz, 1H), 4.32(q, J=7.1Hz, 2H), 7.20(d, J=7.8 Hz, 1H), 7.41 (s, 1H), 7.46 (d, J=7.8 Hz, 1H),7.52(d, J=8.4 Hz, 2H), 8.03(d, J=8.3 Hz, 2H).

General Procedure I:4-[(5-Cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2yl-ethynyl]-benzoicacid (Compound 3, General Formula 4)

A solution of4-[(5-cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl]-benzoicacid ethyl ester (Compound 2, 0.065 g, 0.158 mmol) in ethanol (1 mL) andtetrahydrofuran (1 mL) was treated with 1M aqueous sodium hydroxidesolution (1 mL) and heated at 80° C. for 1 h. The volatiles weredistilled off in vacuo and the residue was diluted with saturatedaqueous ammonium chloride solution and extracted with ethyl acetate(×2). The combined organic extract was dried over anhydrous sodiumsulfate, filtered and evaporated in vacuo to afford a solid that waswashed with dichoromethane and dried to afford the title compound (0.029g, 38%) as a white solid.

¹H-NMR (300 MHz, CD₃COCD₃): δ 0.35-0.51(m, 4H), 1.26(s, 4H), 1.29 (s,4H), 1.60-1.82(m, 2H), 1.88-2.02(m, 2H), 2.02-2.15 (m, 1H), 2.10 (s, 3H), 3.93 (t, J=8.0 Hz, 1H), 7.26(dd, J=1.5, 8.2 Hz, 1H), 7.51 (d, J=1.5Hz, 1 H), 7.52(d, J=8.2 Hz, 1H), 7.62(d, J=8.5 Hz, 2H), 8.02(d, J=8.2Hz, 2H).

4-[(8,8-Dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl)-phenyl]-aceticacid methyl ester (Compound 4, General Formula 8)

Following general procedure F and using6-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-1-one (Intermediate13, 0.312 g, 1.5 mmol), 4-iodo phenyl acetic acid methyl ester (ReagentB, 0.50 g, 1.8 mmol), triethyl amine (7 mL), anhydrous tetrahydrofuran(3 mL), copper(I)iodide (0.04 g, 0.2 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.1 5 g, 0.213 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using 16-20% ethyl acetate in hexane as the eluent, the title compoundwas obtained as a pale yellow solid (0.42 g, 76%).

¹H-NMR (300 MHz, CDCl₃):δ 1.42(s, 6H), 2.04(t, J=6.7 Hz, 2H), 2.74(t,J=6.7 Hz, 2H), 3.66(s, 2H), 3.71(s, 4H), 7.29 (d, J=8.2 Hz, 2H),7.43(dd, J=1.5, 7.9 Hz, 1H), 7.52 (d, J=8.2 Hz, 2H), 7.57 (d, J=1.5 Hz,1H), 8.00(d, J=8.2 Hz, 1H).

General Procedure J:4-[(8,8-Dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl)-phenyl]-aceticacid (Compound 5, General Formula 8)

A solution of4-[(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)-phenyl]-aceticacid methyl ester (Compound 4, 0.1 g, 0.28 mmol) in a mixture ofmethanol (2 mL), tetrahydrofuran (3.5 mL) and water (1.5mL) was treatedwith lithium hydroxide monohydrate (0.11 g, 2.62 mmol) and the resultingreaction mixture was stirred at ambient temperature for 3 h. Thevolatiles were distilled off in vacuo and the residue was diluted withwater and dilute hydrochloric acid and extracted with ethyl acetate(×3). The combined organic phase was dried over anhydrous sodiumsulfate, filtered and evaporated in vacuo to afford the title compoundas a pale yellow solid (0.088 g, 92%).

¹H-NMR (300 MHz, CDCl₃): δ 1.41(s, 6H), 2.02(t, J=6.7 Hz, 2H), 2.74(t,J=6.8 Hz, 2H), 3.68(s, 2H), 7.28 (d, J=8.2 Hz, 2H), 7.42(dd, J=1.5, 8.2Hz, 1H), 7.52 (d, J=8.2 Hz, 2H), 7.56 (d, J=1.5 Hz, 1H), 7.99(d, J=8.2Hz, 1H).

4-[(5-(Cyclopropyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl)-phenyl]-aceticacid methyl ester (Compound 6, General Formula

Following general procedure G and using4-[(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl)-phenyl]-aceticacid methyl ester (Compound 4, 0.2 g, 0.54 mmol), dichloromethane (4mL), acetonitrile(2 mL), cyclopropyl amine(1 mL, 14.45 mmol), aceticacid (1 mL)and sodium cyanoborohydride (0.16 g, 2.54 mmol) followed byflash column chromatography over silica gel (230-400 mesh) using 30%ethyl acetate in hexane as the eluent the title compound was obtained asa pale yellow oil (0.22 g, 99%).

¹H-NMR (300 MHz, CDCl₃): δ 0.38-0.60 (m, 4H), 1.26(s, 4H), 1.33(s, 4 H),1.50-1.59(m, 1H), 1.79-2.10 (m, 4H), 2.25(m, 1H), 3.63(s, 2H), 3.69(s,3H), 3.79(t, J=4.8 Hz, 1H), 7.20-7.32 (m, 4H), 7.47(s, 1H), 7.58(d,J=8.2 Hz, 2H).

4-[(5-(Cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl)-phenyl]-aceticacid methyl ester (Compound 7, General Formula 4)

Following general procedure H and using4-[(5-(cyclopropyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)-phenyl]-aceticacid methyl ester (Compound 6, 0.15 g, 0.37 mmol), acetone (5 mL),potassium carbonate (1.1 g, 7.95 mmol) and methyl iodide (1 mL, 16mmol), the following work-up was used. The volatiles were distilled offin vacuo and the residue was diluted with water and extracted withdichloromethane (×2). The combined organic extract was dried overanhydrous sodium sulfate, filtered and evaporated in vacuo to afford thetitle compound (0. 148 g, 97%).

¹H-NMR (300 MHz, CDCl₃): δ 0.38-0.58(m, 4H), 1.27(s, 4H), 1.31 (s, 4 H),1.68-1.81(m, 2H), 1.85-1.98(m, 2H), 2.08-2.15 (m, 1H), 2.12 (s, 4H),3.62(s, 2H), 3.69(s, 4H), 3.94 (t, J=7.9 Hz, 1H), 7.24(d, J=8.2 Hz, 1H),7.24 (d, J=8.2 Hz, 2H), 7.44-7.51(m, 4H).

4-[(5-(Cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl)-phenyl]-aceticacid (Compound 8, General Formula 4)

Following general procedure J and using4-[(5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2ylethynyl)-phenyl]-aceticacid methyl ester (Compound 7, 0.148 g, 0.357 mmol), methanol (2 mL),tetrahydrofuran (4 mL), water (1 mL) and lithium hydroxide monohydrate(0.25 g, 5.95 mmol) followed by flash column chromatography over silicagel (230-400 mesh) using 30-75% ethyl acetate in hexane as the eluent,the title compound was obtained as a white solid (0.08 g, 56%).

¹H-NMR (300 MHz, CDCl₃): δ 0.52-0.54(m, 2H), 0.68-0.70(m, 2H), 1.27(s,3H), 1.29(s, 4H), 1.63-1.80(m, 2H), 1.95-2.17(m, 2H), 2.19-2.24(m, 1 H),2.24(s, 4H), 3.60(s, 2H), 4.18(t, J=7.7 Hz, 1H), 7.24(dd, J=1.5, 8.2 Hz,1H), 7.26 (d, J=8.2 Hz, 2H), 7.43 (d, J=8.2 Hz, 1H), 7.47(s, 1H),7.47(d, J=8.2 Hz, 2H), 10.37(br s, 1H).

2-Fluoro-4-[(88-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl]benzoic acidethyl ester (Compound 9, General Formula 8)

A solution of4,4-dimethyl-6-trifluromethylsulfonyloxy-1,2,3,4-tetrahydronaphthalene-1-one(Intermediate 11, 0.3 g, 0.9 mmol), copper(I)iodide (0.057 g, 0.3 mmol)and ethyl-2-fluoro-4-ethynyl-benzoate (Reagent D, 0.44 g, 2.27 mmol) intriethyl amine (2 mL) and tetrahydrofuran (3 mL) was sparged with argonfor 5 minutes and treated withdichlorobis(triphenylphosphine)palladium(II) (0.135 g, 0.192 mmol) andstirred at room temperature overnight and then refluxed for 2 h. It wasthen cooled to ambient temperature, diluted with diethyl ether andfiltered over a bed of celite. The filtrate was evaporated in vacuo toan oil which was subjected to flash column chromatography over silicagel (230-400 mesh) using 10-15% ethyl acetate in hexane as the eluent toafford the title compound as a yellow solid (0.22 g, 67%).

¹H-NMR (300 MHz, CDCl₃): δ 1.38 (t, J=7.0 Hz, 4H), 1.39(s, 6H), 2.01 (t,J=6.7 Hz, 2H), 2.71(t, J=6.7 Hz, 2H), 4.37(q, J=7 Hz, 2H), 7.28(dd,J=0.9, 10 Hz, 1H), 7.34(dd, J=0.9, 8.2 Hz, 1H), 7.41 (dd, J=1.5, 8.2 Hz,1H), 7.57(d, J=0.9 Hz), 7.90(t, J=7.9 Hz, 1H), 7.93 (d, J=7.9 Hz, 1H).

2-Fluoro-4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2yl-ethynyl)-benzoicacid (Compound 10, General Formula 8)

A solution of2-fluoro-4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl)benzoicacid ethyl ester (Compound 9, 0.1 g, 0.274 mmol) in ethanol(4 mL),methanol (2 mL) and tetrahydrofuran (2 mL) was treated with 1M aqueoussodium hydroxide solution and heated at 70° C. for 1 h. The volatileswere distilled off in vacuo and the residue was diluted with water anddilute hydrochloric acid and extracted with ethyl acetate (×2). Thecombined organic extract was dried over anhydrous sodium sulfate,filtered and evaporated in vacuo to afford a solid that wasrecrystallized from hot aqueous acetonitrile to afford the titlecompound (0.025 g, 27%).

¹H-NMR (300 MHz, CDCl₃): δ 1.43(s, 6H), 2.05(t, J=6.9 Hz, 2H), 2.76(t,J=6.9 Hz, 2H), 7.26-7.47(m, 4H), 7.60(d, J=1.1 Hz, 1H), 7.99-8.05(m,2H).

4-[5-(Cyclopropyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl]-2-fluoro-benzoicacid ethyl ester (Compound 11, General Formula

Following general procedure G and using2-fluoro-4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)-benzoicacid ethyl ester (Compound 9, 0.132 g, 0.3 mmol), dichloromethane (4mL), acetonitrile(2 mL), cyclopropyl amine(1 mL, 14.45 mmol), aceticacid (1 mL)and sodium cyanoborohydride (0.18 g, 2.86 mmol) followed byflash column chromatography over silica gel (230-400 mesh) using 16-20%ethyl acetate in hexane as the eluent, the title compound was obtainedas a pale yellow oil (0.1 g, 82%).

¹H-NMR (300 MHz, CDCl₃):δ 0.36-0.54 (m, 4H), 1.27(s, 4H), 1.33(s, 4 H),1.40(t, J=7.0 Hz, 4H), 1.54-1.61(m, 2H), 1.82-2.05 (m, 2H), 2.26(m, 1H), 3.79 (t, J=4.9 Hz, 1H), 4.39(q, J=7.1 Hz, 2H), 7.26-7.50(m, 4H),7.87(s, 1H), 7.92 (t, J=7.9 Hz, 1H).

4-[5-(Cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl]-2-fluorobenzoic acid ethyl ester (Compound 12, General Formula 4)

Following general procedure H and using4-[5-(cyclopropyl-methyl-amino)8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl]-2-fluoro-benzoicacid ethyl ester (Compound 11, 0.1 g, 0.246 mmol), acetone (4 mL),potassium carbonate (0.917 g, 6.63 mmol) and methyl iodide (0.8 mL, 11mmol), the following work-up was used. The volatiles were distilled offin vacuo and the residue was diluted with water and extracted withdichloromethane (×2). The combined organic extract was dried overanhydrous sodium sulfate, filtered and evaporated in vacuo to an oil.Flash column chromatography over silica gel (230-400 mesh) using 8-10%ethyl acetate in hexane as the eluent afforded the title compound as apale yellow oil (0.102 g, 98%).

¹H-NMR (300 MHz, CDCl₃): δ 0.39-0.62 (m, 4H), 1.29(s, 4H), 1.34(s, 4 H),1.42(t, J=6.9 Hz, 4H), 1.65-1.82(m, 2H), 1.85-2.02 (m, 2H), 2.02-2.10(m,1H), 2.15(s, 4H), 3.97(t, J=7.7 Hz, 1H), 4.42(q, J=7.0 Hz, 2H),7.28-7.36 (m, 4H), 7.59(s, 1H), 7.55(d, J=7.9 Hz, 2H), 7.92 (t, J=7.5Hz, 1H).

4-[5-(Cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl]-2-fluorobenzoic acid (Compound 13, General Formula 4)

Following general procedure I and using4-[(5-cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl]-2-fluoro-benzoicacid ethyl ester (Compound 12, 0.102 g, 0.23 mmol), ethanol (4 mL) and1M aqueous sodium hydroxide solution (2 mL) followed by flash columnchromatography over silica gel (230-400 mesh) 30% ethyl acetate inhexane as the eluent, the title compound was obtained as an off-whitesolid(0.015 g, 16%).

¹H-NMR (300 MHz, CDCl₃): δ 0.54-0.65 (m, 4H), 1.29 (s, 4H), 1.32 (s, 4H), 1.68-1.83 (m, 2H), 1.97-2.05 (m, 2H), 2.18-2.25 (m, 1H), 2.25 (s,4H), 4.13 (t, J=6.7 Hz, 1H), 7.26-7.30 (m, 2H), 7.34 (dd, J=1.5, 7.9 Hz,1H), 7.48 (d, J=1.8 Hz, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.95 (t, J=7.9 Hz,1H).

[2-Fluoro-4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl)-phenyl]aceticacid ethyl ester (Compound 14, General Formula 8)

Following general procedure F and using6-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydro-naphthalene-1-one(Intermediate 13, 0.298 g, 1.43 mmol), 2-fluoro-4-iodo phenyl aceticacid ethyl ester (Reagent C, 0.44 g, 1.43 mmol), triethyl amine(Intermediate 13, 3 mL), anhydrous tetrahydrofuran (7mL),copper(I)iodide (0.4 g, 0.2 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.15 g, 0.213 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using 14-16% ethyl acetate in hexane as the eluent, the title compoundwas obtained as an oil (0.43 g, 77%).

¹H-NMR (300 MHz, CDCl₃): δ 1.26(t, J=7.2 Hz, 4H), 1.41(s, 6H), 2.04(t,J=6.7 Hz, 2H), 2.74(t, J=6.7 Hz, 2H), 3.68(s, 2H), 4.18(q, J=7.1 Hz, 2H), 7.23-7.57(m, 4H), 7.59 (d, J=1.5 Hz, 1H), 7.99(d, J=7.9 Hz, 1H).

[2-Fluoro-4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl)phenyl]-aceticacid (Compound 15, General Formula 8)

Following general procedure J and using[2-fluoro-4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-ylenthynyl)phenyl]acetic acid methyl ester (Compound 14, 0.18 g, 0.48 mmol),methanol (4 mL), tetrahydrofuran (8 mL), water (2 mL) and lithiumhydroxide monohydrate (0.2 g, 4.76 mmol) followed by flash columnchromatography over silica gel (230-400 mesh) using 50-100% ethylacetate in hexane as the eluent, the title compound was obtained as adirty white solid (0.068 g, 41%).

¹H-NMR (300 MHz, CDCl₃): δ 1.41(s, 6H), 2.03(t, J=6.7 Hz, 2H), 2.74(t,J=6.8 Hz, 2H), 3.73(s, 2H), 7.24-7.32(m, 3H), 7.42(dd, J=1.5, 7.9 Hz,1H), 7.56 (s, 1H), 7.99(d, J=7.9 Hz, 1H), 9.40-10.00 (br s, 1H).

[4-(5-(Cyclopropyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl)-2-fluoro-phenyl]aceticacid ethyl ester (Compound 16, General Formula 4)

Following general procedure G and using[2-fluoro-4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)phenyl]acetic acid ethyl ester (Compound 14, 0.258 g, 0.68 mmol),dichloromethane (4 mL), acetonitrile(2 mL), cyclopropyl amine(1 mL,14.45 mmol), acetic acid (1 mL) and sodium cyanoborohydride (0.266 g,4.23 mmol) followed by flash column chromatography over silica gel(230-400 mesh) using 16-20-25% ethyl acetate in hexane as the eluent,the title compound was obtained as a pale yellow oil (0.21 g, 73%).

¹H-NMR (300 MHz, CDCl₃):δ 0.35-0.54 (m, 4H), 1.25(t, J=7.1 Hz, 3H),1.26(s, 3H), 1.32(s, 3H), 1.53-1.64(m, 1H), 1.82-2.05 (m, 3H),2.21-2.28(m, 1H), 3.65(s, 2H), 3.78(t, J=5.0 Hz, 1H), 4.17(q, J=7.1 Hz,2H), 7.19-7.41 (m, 5H), 7.47(d, J=1.5 Hz, 1H).

[4-(5-(Cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl)-2-fluoro-phenyl]-aceticacid ethyl ester (Compound 17, General Formula 8)

Following general procedure H and using[4-((5-cyclopropyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2ylethynyl)-2-fluoro-phenyl]aceticacid ethyl ester (Compound 16, 0.21 g, 0.5 mmol), acetone (5 mL),potassium carbonate (1.13 g, 8.17 mmol) and methyl iodide (0.5mL, 8mmol), the following work-up was used. The volatiles were distilled offin vacuo and the residue was diluted with water and extracted withdichloromethane (×2). The combined organic extract was dried overanhydrous sodium sulfate, filtered and evaporated in vacuo to afford anoil. Flash column chromatography over silica gel (230-400 mesh) using 8%ethyl acetate in hexane as the eluent afforded the title compound (0.15g, 69%).

¹H-NMR (300 MHz, CDCl₃): δ 0.39-0.53(m, 4H), 1.27(s, 3H), 1.31 (s, 3H),1.66-1.81(m, 2H), 1.89-2.05(m, 2H), 2.08-2.13 (m, 1H), 2.13 (s, 3H),3.62(s, 2H), 3.94 (t, J=8.0 Hz, 1H), 4.16(q, J=7.1 Hz, 2H), 7.20-7.29(m,4H), 7.44(d, J=1.5 Hz, 1H), 7.51 (d, J=8.2 Hz, 1H).

[4-(5-(Cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl)-2-fluoro-phenyl]-aceticacid (Compound 18, General Formula 4)

Following general procedure J and using[4-(5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)-2fluoro-phenyl]-aceticacid ethyl ester (Compound 17, 0.025 g, 0.059 mmol), methanol (1 mL),tetrahydrofuran (1 mL), water (0.5 mL) and lithium hydroxide monohydrate(0.060 g, 1.43 mmol), the title compound was obtained as a white solid(0.023 g, 95%).

¹H-NMR (300 MHz, CDCl₃):δ 0.52-0.54(m, 2H), 0.68-0.70(m, 2H), 1.27(s,3H), 1.29(s, 3H), 1.63-1.80(m, 2H), 1.95-2.17(m, 2H), 2.19-2.24(m, 1 H),2.24(s, 3H), 3.60(s, 2H), 4.18(t, J=7.7 Hz, 1H), 7.19-7.28(m, 4H), 7.45(d, J=1.5 Hz, 1H), 7.49(d, J=8.2 Hz, 1H), 8.80-9.20(br s, 1H).

General Procedure K: 8,8-Dimethyl-5,6,7,8-tetrahydro-naphthalene-1-one-2-carboxylic acid-4-(tert-butoxycarbonylmethyl)phenyl esterCompound 19, General Formula 8)

A solution of4,4-dimethyl-6-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydronaphthalene-1-one(Intermediate 11, 0.14 g, 0.434 mmol), t-butyl-4-hydroxy-phenyl acetate(Reagent E, 0.14 g, 0.673 mmol), palladium acetate (0.054 g, 0.24 mmol)and 1,3-bis(diphenylphosphino)propane (0.082 g, 0.2 mmol) in a mixtureof dimethylsulfoxide (1 mL), 1,2-dichloroethane (1.5 mL) and triethylamine (1 mL) was heated at 70° C. under an atmosphere of carbon monoxideovernight. The volatiles were distilled of in vacuo and the residue wasdiluted with water and extracted with diethyl ether (×3). The combinedorganic extract was dried over anhydrous magnesium sulfate, filtered andevaporated in vacuo to an oil which was subjected to flash columnchromatography over silica gel (230-400 mesh) using 15% ethyl acetate inhexane as the eluent to afford the title compound (0.11 g, 53%).

¹H-NMR (300 MHz, CDCl₃): δ 1.44(s, 3H), 1.44(s, 9H), 1.46 (s, 3H),2.07(t, J=6.9 Hz, 2H), 2.76(t, J=6.8 Hz, 2H), 3.55(s, 2H), 7.17 (d,J=8.5 Hz, 2 H), 7.35(d, J=8.5 Hz, 2H), 8.05-8.13(m,2H), 8.25 (d, J=1.5Hz, 1H).

8,8-Dimethyl-5-oxo-5 6,7,8-tetrahydro-naphthalene-2-carboxylicacid-4-(carboxymethyl)phenyl ester (Compound 20, General Formula 8)

A solution of8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid4-(tert-butoxycarbonylmethyl)phenyl ester (Compound 19, 0.11 g, 0.229mmol) in dichloromethane (2 mL) was treated with trifluoroacetic acid(0.85 mL and stirred at ambient temperature for 2.5 h. The volatileswere distilled off in vacuo and the residue was diluted with water andextracted with ethyl acetate (×3). The combined organic phase was driedover anhydrous sodium sulfate, filtered and evaporated in vacuo toafford a solid which was subjected to flash column chromatography oversilica gel (230-400 mesh) using ethyl acetate as the eluent to affordthe title compound (0.024 g, 25%).

¹H-NMR (300 MHz, CDCl₃): δ 1.46 (s, 6H), 2.08(t, J=6.7 Hz, 2H), 2.80(t,J=6.7 Hz, 2H), 3.70(s, 2H), 7.20(d, J=8.5 Hz, 2H), 7.37(d, J=8.5 Hz, 2H), 8.08(dd, J=1.4, 8.2 Hz, 1H), 8.14 (d, J=8.2 Hz, 1H), 8.24 (d,J=1.2Hz, 1 H).

5-Methoxy-3.3-dimethyl-indane (Intermediate 15)

Following general procedure A and using titanium tetrachloride (5.5mL,50 mmoL), anhydrous dichloromethane (80 mL), 2M solution dimethylzinc (50 mL) in toluene and a solution of 6-methoxy-indane-1-one (4.05g, 25 mmol) in dichloromethane (10 mL) the title compound was obtainedas an oil (3.13 g, 71%).

¹H-NMR (300 MHz, CDCl₃):δ 1.37 (s, 6H), 2.04(t, J=7.2 Hz, 2H), 2.94(t,J=7.2 Hz, 2H), 3.89(s, 3H), 6.82(d, J=2.1 Hz, 1H), 7.28(dd, J=2.1, 7.0Hz, 1H), 7.35 (d, J=7.0 Hz, 1H).

5-Methoxy-3.3-dimethyl-indane-1-one (Intermediate 16)

Following general procedure B and using 5-methoxy-3,3-dimethyl indane(Intermediate 15, 3.13 g, 17.78 mmol) in 20 mL of glacial acetic acidand a solution of chromium trioxide (3.91 g, 39.1 mmol) in 20 mL ofacetic acid and 20 mL of water the title compound was obtained as aviscous yellow oil (3.3 g, 97%).

¹H-NMR (300 MHz, CDCl₃):δ 1.37 (s, 6H), 2.54 (s, 2H), 3.87(s, 3H),6.86-6.87 (m, 2H), 7.60 (d, J=7.0 Hz, 1H).

6-Methoxy-4,4-dimethyl-1,2,34-tetrahydro-isoquinoline-1-one(Intermediate 17)

A solution of 5-methoxy-3,3-dimethyl-indane-1-one (Intermediate 16, 3.3g, 17.4 mmol) in benzene (50 mL) was treated with concentrated sulfuricacid (10 mL) and heated to 60° C. Sodium azide (1.95 g, 30 mmol) wasadded in small portions and after the addition was complete, thereaction mixture was heated further for 4 h. It was then cooled, dilutedwith water and extracted with chloroform (×3). The combined organicphase was dried over anhydrous magnesium sulfate, filtered andevaporated in vacuo to afford the title compound as a brown solid (3.5g, quantitative by weight).

¹H-NMR (300 MHz, CDCl₃): δ 1.31 (s, 6H), 3.28 (s, 2H), 3.83(s, 3H), 6.78(d, J=2.6 Hz, 1H), 6.82(dd, J=2.6 Hz, 8.5 Hz, 1H), 7.59 (s, 1H), 8.02(d, J=8.2 Hz, 1H).

6-Methoxy-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline (Intermediate 18)

A solution of6-methoxy-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline-1-one(Intermediate 17, 3.5 g, 17 mmol) in 100 mL of anhydrous tetrahydrofuranwas treated with lithium aluminum hydride (1.3 g, 34.25 mmol) in smallportions and the resulting suspension was refluxed for 3 hours underargon. The reaction mixture was then cooled in an ice bath andcautiously quenched with saturated aqueous sodium sulfate solution andthe resulting slurry was filtered and the filter-cake washed well withethyl acetate. The filtrate and washings were evaporated in vacuo to abrown oil which was dissolved in chloroform, the solution was dried overanhydrous magnesium sulfate, filtered and evaporated in vacuo to affordthe title compound (3.2 g, ˜100%).

¹H-NMR (300 MHz, CDCl₃): δ 1.27 (s, 6H), 2.22 (s, 1H), 2.84 (s, 2H),3.79 (s, 3H), 3.95 (s, 2H), 6.68(dd, J=2.4 Hz, 8.3 Hz, 1H), 6.86(d,J=2.4 Hz, 1 H), 6.91 (d, J=8.3 Hz, 1H).

6-Methoxy-4,4-dimethyl-1 2,3,4-tetrahydro-isoquinoline-2-carbaldehyde(Intermediate 19)

A solution of 6-methoxy-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline(Intermediate 18, 3.2 g, 16.7 mmol) in anhydrous dichloromethane (40 mL)was treated with formic acid (1 mL, 26.5 mmol) followed1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.9 g,20.34 mmol) and the resulting solution was stirred at ambienttemperature overnight. It was then diluted with chloroform and washedwith water (×1) and brine (×1), dried over anhydrous magnesium sulfate,filtered and evaporated in vacuo to afford the title compound as palebrown viscous oil (3.26 g, 90%).

¹H-NMR (300 MHz, CDCl₃): δ 1.28 (s, 6H), 3.32 (s, 0.7H), 3.54 (s, 0.3H), 3.79(s, 3H), 4.54 (s, 0.3H), 4.66(s, 0.7H), 6.71(dd, J=2.6 Hz, 8.2Hz, 1 H), 6.85-6.97(m, 1H), 7.02-7.27(m, 1H), 8.15(s, 0.7H), 8.34(s,0.3H), 8.40-8.80 (br s, 1H).

6-Hydroxy-4,4-dimethyl-1.2,3 4-tetrahydro-isoquinoline-2-carbaldehyde(Intermediate 20) A stirred, cooled (−78° C.) solution of6-methoxy-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline-2-carbaldehyde(Intermediate 19, 3.26 g, 15 mmol) in anhydrous dichloromethane (15 mL)was treated with 1M solution of boron tribromide in dichloromethane (50mL) stirred at ambient temperature for 3 h. It was then cooled again to78° C. and quenched carefully with saturated aqueous sodium carbonatesolution, diluted with water and the aqueous phase was extracted withethyl acetate (×2). The combined organic extract was dried overanhydrous sodium sulfate, filtered and evaporated in vacuo to afford thetitle compound as a solid foam (3 g, 99%).

¹H-NMR (300 MHz, CDCl₃): δ 1.23 (s, 6H), 3.31 (s, 0.7H), 3.54 (s, 0.3H), 4.51 (s, 0.3H), 4.64 (s, 0.7H), 6.70-6.75(m, 1H), 6.84-6.90(m, 2H),7.50-7.80(br s, 1H), 8.12(s, 0.7H), 8.32(s, 0.3H).

2-Cyclopropyl-6-hydroxy-4,4-dimethyl -1,2,3,4-tetrahydro-isoquinoline(Intermediate 21)

A stirred, cooled (0° C.)solution of6-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline-2-carbaldehyde(Intermediate 20, 2.3 g, 11.21 mmol) in anhydrous tetrahydrofuran (40mL) under argon was treated with titanium tetra-iso-propoxide (8.28 mL,28 mmol) followed by 3M solution of ethyl magnesium bromide in diethylether (18.7 mL) and the reaction mixture was then heated at 55° C.overnight. It was then cooled in an ice-bath, quenched with saturatedaqueous ammonium chloride solution and extracted with diethyl ether(×2). The combined organic phase was dried over anhydrous sodiumsulfate, filtered and evaporated in vacuo to afford a yellow oily solid.Flash column chromatography over silica gel (230-400 mesh) using 10-20%ethyl acetate in hexane as the eluent afforded the title compound as apale yellow solid (1.55 g, 63%).

¹H-NMR (300 MHz, CD₃COCD₃): δ 0.016-0.16(m, 4H), 0.847 (s, 6H), 1.37 (m,1H), 2.20(s, 2H), 3.25 (s, 2H), 6.22(dd, J=2.4, 8.2 Hz, 1H), 6.41(d,J=2.6 Hz, 1H), 6.47(d, J=8.2 Hz, 1H), 7.62(s, 1H).

2-Cyclopropyl-4,4-dimethyl-6-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydro-isoquinoline(Intermediate 22)

Following general procedure C and using2-cyclopropyl-6-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline(Intermediate 21, 1.5 g, 6.9 mmol) in anhydrous dichloromethane (30 mL),triethyl amine (1.5 mL, 10.39 mmol) and[N,N′-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine (2.75 g, 7mmol) followed by flash column chromatography over silica gel (230-400mesh) using 8% ethyl acetate in hexane as the eluent the title compoundwas obtained (2.23 g, 92%) as oil. ¹H-NMR (300 MHz, CDCl₃): δ0.42-0.54(m, 4H), 1.25(s, 6H), 1.76(m, 1H), 2.62(s, 2H), 3.74(s, 2H),6.98(dd, J=2.3, 8.4 Hz, 1H), 7.16(d, J=8.2 Hz, 1H), 7.14(d, J=2.3 Hz,1H).

Ethyl-2-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate(Intermediate 23)

Following general procedure K and using2-cyclopropyl-4,4-dimethyl-6-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydro-isoquinoline(Intermediate 22, 1.6 g, 4.6 mmol), palladium acetate (0.127 g, 0.56mmol), 1,3-bis(diphenylphosphino)propane (0.160 g, 0.39 mmol),dimethylsulfoxide (2 mL), 1,2-dichloroethane (5 mL), triethyl amine (2mL) , ethanol (5 mL) and an atmosphere of carbon monoxide followed byflash column chromatography over silica gel (230-400 mesh) using 10%ethyl acetate in hexane as the eluent the title compound was obtained asan oil (1 g, 79%).

¹H-NMR (300 MHz, CDCl₃):δ 0.44-0.54(m, 4H), 1.27(s, 6H), 1.38 (t, J=7Hz, 3H), 1.73(m, 1H), 2.62(s, 2H), 3.76(s, 2H), 4.35 (q, J=7.1 Hz, 2H7.04(d, J=7.9 Hz, 1H), 7.74 (dd, J=1.7, 7.9 Hz, 1H), 7.97(d, J=1.8 Hz,1H).

2-Cyclopropyl-6-hydroxymethyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline(Intermediate 24)

A stirred cooled (−78° C.)solution ofethyl-2-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (Intermediate 23, 1 g, 3.66 mmol) inanhydrous dichloromethane (20 mL) under argon was treated with a 1Msolution of di-iso-butyl aluminum hydride in dichloromethane (10 mL) andthe reaction mixture was warmed to −20° C. over 1 h. It was thenquenched with saturated aqueous ammonium chloride solution and dilutedwith dichloromethane and filtered over a bed of celite. The phases wereseparated and the aqueous phase was extracted with dichloromethane (×1).The combined organic extract was dried over anhydrous sodium sulfate,filtered and evaporated in vacuo to afford the title compound as aviscous oil (0.74 g, 87%).

¹H-NMR (300 MHz, CDCl₃): δ 0.45-0.53(m, 4H), 1.25(s, 6H), 1.72-1.82(m,2H), 2.61(s, 2H), 3.73(s, 2H), 4.61 (d, J=5 Hz, 2H), 6.98(d, J=7.9 Hz,1H), 7.07 (dd, J=1.5, 7.6 Hz, 1H), 7.27(s, 1H).

2-Cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-6-carbaldehyde(Intermediate 25)

A solution of2-cyclopropyl-6-hydroxymethyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline(Intermediate 24, 0.74 g, 3.2 mmol) in dichloromethane (10 mL) andacetonitrile (2.5 mL) was treated sequentially with 4A° molecular sievespowder (1.06 g), tetra-n-propyl ammonium perruthenate (0.050 g, 0.14mmol) and N-methyl morpholine N-oxide (1.1 g, 9.8 mmol). After stirringat ambient temperature for 0.5 h, it was diluted with 5 mL of hexane andsubjected to flash column chromatography over silica gel (230-400 mesh)using 10% ethyl acetate in hexane as the eluent to afford the titlecompound as an oil (0.27 g, 37%).

¹H-NMR (300 MHz, CDCl₃):δ 0.44-0.56(m, 4H), 1.30(s, 6H), 1.79(m, 1H),2.66(s, 2H), 3.82(s, 2H), 7.17(d, J=7.9 Hz, 1H), 7.60 (dd, J=1.6, 7.9Hz, 1H), 7.82(d, J=1.8 Hz, 1H), 9.95 (s, 1H).

6-(2,2-Dibromo-vinyl)-2-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline(Intermediate 26)

A stirred, cooled (ice-bath) solution of triphenyl phosphine (0.53 g, 2mmol) in anhydrous dichloromethane was treated with carbon tetrabromide(0.35 g, 1 mmol) under argon. After 0.5 h, a solution of2-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-6-carboxaldehyde(Intermediate 25, 0.13 g, 0.57 mmol) in dichloromethane (2 mL) wascannulated into the reaction mixture. After 1.5 h between 0° C. and 10°C., the reaction mixture was subjected to flash column chromatographyover silica gel (230-400 mesh) using 3-5% ethyl acetate in hexane as theeluent to afford the title compound as a viscous, pale yellow oil (0.18g, 82%).

¹H-NMR (300 MHz, CDCl₃):δ 0.49-0.57(m, 4H), 1.31(s, 6H), 1.80(m, 1H),2.67(s, 2H), 3.77(s, 2H), 7.04(d, J=7.9 Hz, 1H), 7.29 (dd, J=1.7, 7.9Hz, 1H), 7.49 (s, 1H), 7.50(d, J=1.7 Hz, 1H).

2-Cyclopropyl-6-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline(Intermediate 27)

A stirred, cooled (−78° C.) solution of6-(2,2-dibromo-vinyl)-2-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-6-carboxaldehyde(Intermediate 26, 0.1 8 g, 0.47 mmol) in tetrahydrofuran (2 mL) wastreated with 1.6M solution of n-butyl lithium (0.6 mL, 0.96 mmol) underargon. The reaction mixture was allowed to warm to −20° C. over 1.5 h,quenched with saturated aqueous ammonium chloride solution and extractedwith diethyl ether (×2). The combined organic phase was dried overanhydrous magnesium sulfate, filtered and evaporated in vacuo to affordthe title compound as an oil (0.1 g, 94%).

¹H-NMR (300 MHz, CDCl₃):δ 0.47-0.55(m, 4H), 1.28(s, 6H), 1.77(m, 1H),2.63(s, 2H), 3.05(s, 1H), 3.67(s, 2H), 6.98(d, J=7.6 Hz, 1H), 7.26 (dd,J=1.5, 7.9 Hz, 1H), 7.46(d, J=1.5 Hz, 1H).

[4-(2-Cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-6-yl-ethynyl)-2-fluoro-phenyl]-aceticacid ethyl ester (Compound 21, General Formula 3)

Following general procedure F and using2-cyclopropyl-6-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline(Intermediate27, 0.1 3 g, 0.571 mmol), 2-fluoro-4-iodo phenyl acetic acid ethyl ester(Reagent C, 0.16 g, 0.52 mmol), triethyl amine (0.8 mL), anhydroustetrahydrofuran (2 mL), copper(I)iodide (0.051 g, 0.27 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.1 g, 0.14 mmol) followedby flash column chromatography over silica gel (230-400 mesh) using 10%ethyl acetate in hexane as the eluent, 0.1 g of the title compound wasobtained as an oil. It was further purified by preparative normal phaseHPLC on a partisil-10 silica column using 10% ethyl acetate in hexane asthe mobile phase (0.055 g, 24%).

¹H-NMR (300 MHz, CDCl₃):δ 0.42-0.51(m, 4H), 1.26(t, J=7.3 Hz, 3H),1.27(s, 6H), 1.75(m, 1H), 2.61(s, 2H), 3.66(s, 2H), 3.74(s, 2H), 4.18(q, J=7.3 Hz, 2H), 6.97 (d, J=7.9 Hz, 1H), 7.20-7.29(m, 4H), 7.45(d,J=1.5 Hz, 1H).

[4-(2-Cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-6-yl-ethynyl)-2-fluoro-phenyl]-aceticacid (Compound 22, General Formula 3)

Following general procedure J and using[4-(2-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-6-ylethynyl)-2-fluoro-phenyl]-aceticacid ethyl ester (Compound 21, 0.055 g, 0.135 mmol), methanol (2 mL),tetrahydrofuran (4 mL), water (1 mL) and lithium hydroxide monohydrate(0.117 g, 2.97 mmol) the title compound was obtained as a pale yellowsolid foam (0.040 g, 78%).

¹H-NMR (300 MHz, CDCl₃): δ 0.52-0.65(m, 4H), 1.27(s, 6H), 1.84(m, 1H),2.71(s, 2H), 3.61(s, 2H), 3.85(s, 2H), 6.98(d, J=7.9 Hz, 1H), 7.06 (t,J=7.6 Hz, 1H), 7.17-7.25(m, 3H), 7.43(d, J=1.2 Hz, 1H), 8.60-9.00(br s,1H).

[4-(2-Cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-6-yl-ethynyl)-phenyl]-aceticacid methyl ester (Compound 23, General Formula 3)

Following general procedure F and using2-cyclopropyl-4,4-dimethyl-6-ethynyl-1,2,3,4-tetrahydro-isoquinoline(Intermediate27, 0.13 g, 0.571 mmol), 4-iodo phenyl acetic acid methyl ester (ReagentB, 0.16 g, 0.58 mmol), triethyl amine (0.5 mL), anhydroustetrahydrofuran (2 mL), copper(I)iodide (0.04 g, 0.21 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.12 g, 0.17 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using 10% ethyl acetate in hexane as the eluent, 0.05 g of the titlecompound was obtained as an oil. It was further purified by preparativenormal phase HPLC on a partisil-10 silica column using 10% ethyl acetatein hexane as the mobile phase (0.01 g, 6%).

¹H-NMR (300 MHz, CDCl₃): δ 0.42-0.58(m, 4H), 1.29(m, 6H), 1.79(m, 1H),2.64(s, 2H), 3.67(s, 3H), 3.72(s, 2H), 3.77(s, 2H), 7.09 (d, J=7.9 Hz,1H), 7.28(dd, J=1.5, 7.9 Hz, 1H), 7.36 (d, J=7.9 Hz, 2H), 7.50 (d, J=1.6Hz, 1H), 7.51(d, J=7.9 Hz, 2H).

[4-(2-Cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-6-yl-ethynyl)-phenyl]-aceticacid

Following general procedure J and using[4-(2-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-6ylethynyl)-phenyl]-aceticacid methyl ester (Compound 23, 0.01 g, 0.027 mmol), methanol (1 mL),tetrahydrofuran (1 mL), water (0.5 mL) and lithium hydroxide monohydrate(0.042 g, 1 mmol) the title compound was obtained as a pale yellow solidfoam (0.0065 g, 68%).

¹H-NMR (300 MHz, CDCl₃): δ 0.35-0.52(m, 4H), 1.24(s, 6H), 1.74(m, 1H),2.59(s, 2H), 3.64(s, 2H), 3.71(s, 2H), 7.03 (d, J=8.2 Hz, 1H), 7.22(dd,J=1.4, 7.9 Hz, 1H), 7.33 (d, J=8.2 Hz, 2H), 7.46 (d, J=8.2 Hz, 2H),7.47(s, 1H).

1-(Iso-propyl-methyl-amino)-6-trimethylsilanylethynyl-4,4-dimethyl-1,2,3,4-tetrahydro-naphthalene(Intermediate 28)

Following general procedure G and using a solution of4,4-dimethyl-6-trimethylsilanylethynyl-1,2,3,4-tetrahydro-naphthalene2-one (Intermediate 12, 0.2 g, 0.78 mmol), dichloromethane (4 mL),acetonitrile (2 mL), acetic acid (1 mL), isopropyl amine (1 mL, 11.74mmol) and sodium cyanoborohydride (0.19 g, 3.02 mmol), after 15 days ofreaction time and work up afforded an intermediate (0.14 g, 60%, 0.47mmol) which was used following general procedure H along with acetone (2mL), potassium carbonate (0.6 g, 4.34 mmol) and methyl iodide (0.5 mL, 8mmol). The crude product after work up was subjected to flash columnchromatography over silica gel (230-400 mesh) using 15% ethyl acetate inhexane as the eluent to afford the title compound as a pale yellow oil(0.14 g, 95%).

¹H-NMR (300 MHz, CDCl₃): δ 0.001(s, 9H), 0.85 (d, J=6.4 Hz, 6H), 0.98(s, 3H), 1.03 (s, 3H), 1.32-1.60 (m, 4H), 1.81(s, 3H), 2.64(heptet,J=6.4 Hz, 1H), 3.65 (dd, J=6.1, 9.4 Hz, 1H), 6.97 (dd, J=1.7, 7.9 Hz,1H), 7.13 (d, J=1.7 Hz, 1H), 7.82 (d, J=7.9 Hz, 1H).

6-Ethynyl-1-(iso-propyl-methyl-amino)-4,4-dimethyl-1,2,3,4-tetrahydro-naphthalene(Intermediate 29)

Following general procedure E and using1-(methyl-iso-propylamino)-4,4-dimethyl-6-trimethylsilanylethynyl-1,2,3,4-tetrahydro-naphthalene(Intermediate 28, 0.14 g, 0.45 mmol), methanol (5 mL), potassiumcarbonate (0.61 g, 4.41 mmol) and ethyl acetate the title compound(0.092 g, 80%) was obtained as an oil.

¹H-NMR (300 MHz, CDCl₃):δ 1.11(d, J=6.4 Hz, 6H), 1.23(s, 3H), 1.28(s,3H), 1.51-1.87 (m, 4H), 2.09(s, 3H), 2.90 (heptet, J=6.4 Hz, 1H),3.00(s, 1H), 3.91 (dd, J=5.8, 10.0 Hz, 1H), 7.25(dd, J=1.7, 8.2 Hz, 1H),7.41 (d, J=1.7 Hz, 1H), 7.70(d, J=8.2 Hz, 1H).

4-[5-(Iso-propyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl)]-benzoicacid ester (Compound 25, General Formula 4)

Following general procedure F and6-ethynyl-1-(iso-propyl-methyl-amino)-4,4-dimethyl-1,2,3,4-tetrahydro-naphthalene(Intermediate 29, 0.092 g, 0.36 mmol), ethyl-4-iodo benzoate (Reagent A,0.12 g, 0.48 mmol), triethyl amine (1 mL), tetrahydrofuran (2 mL),copper(I)iodide (0.028 g, 0.14 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.075 g, 0.11 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using 10-15% ethyl acetate in hexane as the eluent the title compoundwas obtained (0.04 g, 27%).

¹H-NMR (300 MHz, CDCl₃): δ 1.12 (d, J=6.5 Hz, 6H), 1.27 (s, 3H), 1.31(s, 3H), 1.40 (t, J=7.0 Hz, 3H), 1.62-1.89 (m, 4H), 2.10(s, 3H), 2.92(heptet, J=6.4 Hz, 1H), 3.94(dd, J=6.1, 9.7 Hz, 1H), 4.38(q, J=7.1 Hz,2H), 7.31(dd, J=1.4, 8.2 Hz, 1H), 7.46 (d, J=1.7 Hz, 1H), 7.58 (d, J=8.2Hz, 2H), 7.75(d, J=8.2 Hz, 1H), 8.01 (d, J=8.2 Hz, 2H).

4-[5-(Iso-propyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl)]-benzoicacid (Compound 26, General Formula 4)

Following general procedure I and using4-[5-(iso-propyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)]-benzoicacid ethyl ester (Compound 25, 0.04 g, 0.01 mmol), ethanol (2 mL),tetrahydrofuran (1 mL) and 1M aqueous sodium hydroxide solution (1 mL)followed by recrystallization from diethylether-hexane, the titlecompound was obtained as an off-white solid (0.010 g, 27%).

¹H-NMR (300 MHz, CDCl₃): δ 1.30(d, J=6.0 Hz, 6H), 1.31(s, 9H),1.67-1.98(m, 4H), 2.35 (s, 3H), 3.19 (heptet, J=6.4 Hz, 1H), 4.36 (t,J=7.6 Hz, 1H), 7.28(dd, J=1.4, 8.2 Hz, 1H), 7.48 (d, J=1.4 Hz, 1H), 7.55(d, J=8.2 Hz, 2H), 7.81 (d, J=8.2 Hz, 1H), 8.05 (d, J=8.2 Hz, 2H).

[4-(2,2,4,4-Tetramethyl-chroman-6-yl-ethynyl) phenyl] acetic acid methylester (Compound 27, General Formula 8)

Following general procedure F and using6-ethynyl-2,2,4,4-tetramethylchroman (synthesis described in U.S. Pat.Nos. 5,045,551 and 5,616,597 incorporated herein by reference) (0.060 g,0.28 mmol), methyl-4-iodo phenyl acetate (Reagent B, 0.078 g, 0.28mmol), triethyl amine (4 mL), tetrahydrofuran (4 mL), copper(I)iodide(0.030 g, 0.16 mmol) and dichlorobis(triphenylphosphine)palladium(II)(0.11 g, 0.16 mmol) followed by flash column chromatography over silicagel (230-400 mesh) using 5-10% ethyl acetate in hexane as the eluent thetitle compound was obtained (0.047 g, 46%).

¹H NMR (300 MHz, CDCl₃): δ 7.48-7.45 (m, 3H), 7.25-7.23 (m, 3H), 6.75(d, 1H, J=8.2 Hz), 3.70 (s, 3H), 3.62 (s, 2H), 1.84 (s, 2H), 1.36 (s,6H), 1.35 (s, 6H).

General Procedure L: [4-(2,2,4,4-Tetramethyl-chroman-6-yl-ethynyl)phenyl] acetic acid (Compound 28, General Formula 8)

A solution of [4-(2,2,4,4-tetramethyl-chroman-6-yl-ethynyl) phenyl]acetic acid methyl ester (Compound 27, 0.047 g, 0.13 mmol) in 5 mL ofmethanol was treated with 1M sodium hydroxide solution (2 mL) and heatedat 55° C. for 2 h. The volatiles were distilled off in vacuo and theresidue was acidified with 10% hydrochloric acid and extracted withethyl acetate (×2). The combined organic phase was washed with brine(×1), dried over anhydrous sodium sulfate, filtered and evaporated invacuo to a residue which was purified by preparative reverse phase HPLCusing 10% water in acetonitrile as the mobile phase to afford the titlecompound (0.034 g, 82%). ¹H NMR (300 MHz, CDCl₃): δ 7.49-7.45 (m, 3H),7.26-7.22 (m, 3H), 6.75 (d, 1H, J=8.2 Hz), 3.65 (s, 2H), 1.84 (s, 2H),1.36 (s, 6H), 1.35 (s, 6H).

2-Fluoro-4-(2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)-benzoic acidmethyl ester (Compound 29, General Formula 8)

Following general procedure F and using6-ethynyl-2,2,4,4-tetramethylchroman (0.11 g, 0.51 mmol),methyl-2-fluoro-4-iodo-benzoate (Reagent G, 0.14 g, 0.51 mmol), triethylamine (5 mL), tetrahydrofuran(10 mL), copper(I)iodide(0.030 g, 0.16mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.110 g, 0.16mmol) followed by flash column chromatography over silica gel (230-400mesh) using 5-10% ethyl acetate in hexane as the eluent, the titlecompound was obtained (0.14 g, 79%).

¹H NMR (300 MHz, CDCl₃): δ 7.82 (t, 1H, J=7.9 Hz), 7.39 (d, 1H, J=1.8Hz), 7.25-7.16 (m, 3H), 6.69 (d, 1H, J=8.2 Hz), 3.85 (s, 3H), 1.77 (s,2H), 1.29 (s, 6H), 1.28 (s, 6H).

2-Fluoro-4-(2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)-benzoic acid(Compound 30, General Formula 8)

Following general procedure L and using2-fluoro-4-(2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)-benzoic acidmethyl ester (Compound 29, 0.14 g, 0.4 mmol), 5 mL of methanol and 1Msodium hydroxide solution (2 mL) followed by recrystallization fromethyl acetate, the title compound was obtained (0.083 g, 58%).

¹H NMR (300 MHz, CD₃COCD₃): δ 8.00 (t, 1H, J=7.8 Hz), 7.63 (d, 1H, J=2.1Hz), 7.45 (dd, 1H, J=1.5, 7.9 Hz), 7.38 (dd, 1H, J=1.5, 11.4 Hz), 7.32(dd, 1H, J=2.1, 8.2 Hz), 6.81 (d, 1H, J=8.5 Hz), 1.92 (s, 2H), 1.41 (s,6H), 1.38 (s, 6H).

[2-Fluoro-4-(2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)phenyl] aceticacid ethyl ester (Compound 31, General Formula 8)

Following general procedure F and using6-ethynyl-2,2,4,4-tetramethylchroman (0.204 g, 0.95 mmol),ethyl-2-fluoro-4-iodo phenyl acetate (Reagent C, 0.263 g, 0.86 mmol),triethyl amine, tetrahydrofuran, copper(I)iodide (0.025 g, 0.13 mmol)and dichlorobis(triphenylphosphine)palladium(II) (0.075 g, 0.11 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using 5-10% ethyl acetate in hexane as the eluent, the title compoundwas obtained (0.21 g, 62%).

¹H NMR (300 MHz, CDCl₃): δ 7.46 (d, 1H, J=2.1 Hz), 7.25-7.21 (m, 4H),6.69 (d, 1H, J=8.5 Hz), 4.16 (q, 2H, J=7.1 Hz), 3.65 (s, 2H), 1.82 (s,2H), 1.35 (s, 6H), 1.35 (s, 6H), 1.24 (t, 3H, J=7.2 Hz).

[2-Fluoro-4-(2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)phenyl] aceticacid (Compound 32, General Formula 8)

Following general procedure L and using[2-fluoro-4-(2,2,4,4-tetramethyl-chroman-6-ylethynyl)phenyl] acetic acidethyl ester (Compound 31, 0.21 g, 0.58 mmol), 5 mL of methanol and 1Msodium hydroxide solution (2 mL) followed by flash column chromatographyover silica gel (230-400 mesh) using 50% ethyl acetate in hexane, thetitle compound was obtained as a solid (0.184 g, 93%).

¹H NMR (300 MHz, CDCl₃): δ 11.40 (br s, 1H), 7.48 (d, 1H, J=1.8 Hz),7.46-7.16 (m, 4H), 6.76 (d, 1H, J=8.2 Hz), 3.69 (s, 2H), 1.82 (s, 2H),1.34 (s, 12H).

3-Methyl-but-2-enoic acid 4-bromo-phenyl ester:

To a stirred, cooled (ice bath) suspension of sodium hydride (2.4 g, 100mmol) in anhydrous tetrahydrofuran (200 mL), 4-bromo phenol (17.3 g, 100mmol) was added followed by 3,3,-dimethyl acryloyl chloride (11.14 mL,100 mmol). After 4 hours at ambient temperature, the reaction mixturewas poured into brine and extracted with diethyl ether (×2). Thecombined organic phase was dried over anhydrous sodium sulfate, filteredand evaporated in vacuo to afford an oil which was subjected to flashcolumn chromatography over silica gel (230-400 mesh) using 2% ethylacetate in hexane as the eluent to afford the title compound (15 g,59%).

¹H-NMR (300 MHz, CDCl₃):δ 2.00(s, 3H), 2.23(s, 3H), 5.89(s, 1H), 7.00(d,J=8.8 Hz, 2H), 7.49(d, J=8.8 Hz, 2H).

6-Bromo-4,4-dimethyl-chroman-2-one:

A solution of 3-methyl-but-2-enoic acid 4-bromo-phenyl ester (7 g, 27.6mmol) in anhydrous dichloromethane (200 mL) was cooled (ice bath) andtreated with aluminum chloride (6.6 g, 49.6 mmol) and the reactionmixture was stirred overnight at ambient temperature. The reactionmixture was quenched with saturated aqueous sodium bicarbonate solutionand extracted with diethyl ether (×2). The combined organic extract waswashed woth brine (×1), dried over anhydrous sodium sulfate, filteredand evaporated in vacuo to afford an oil which was purified by flashcolumn chromatography over silica gel (230-400 mesh) using 2.5% ethylacetate in hexane as the eluent to afford the title compound (4.2 g,57%).

¹H-NMR (300 MHz, CDCl₃):δ 1.36(s, 6H), 2.62(s, 2H), 6.95(d, J=8.5 Hz,1H), 7.37(dd, J=2.4, 8.5 Hz, 1H), 7.43(d, J=2.3 Hz, 1H).

4-Bromo-2-(3-hydroxy-1,1,3-trimethyl-butyl)-phenol:

A solution of 6-bromo-4,4-dimethyl-chroman-2-one (1 g, 3.92 mmol) inanhydrous tetrahydrofuran (20 mL) was treated with 3M solution of ethylmagnesium bromide (2.6 mL) and stirred at ambient temperature for 2hours. The reaction mixture was poured into cold dilute hydrochloricacid and extracted with ethyl acetate (×2). The combined organic extractwas dried over anhydrous sodium sulfate, filtered and evaporated invacuo to afford a residue which was subjected to flash columnchromatography over silica gel (230-400 mesh) using 10% ethyl acetate inhexane as the eluent to afford the title compound as a pale yellow solid(1.1 g, 100%).

¹H-NMR (300 MHz, CDCl₃):δ 1.14(s, 6H), 1.44(s, 6H), 2.20(s, 2H), 6.49(d,J=8.4 Hz,1H), 7.15(dd, J=2.4, 8.5 Hz, 1H), 7.37(d, J=2.4 Hz, 1H).

6-Bromo-2,2,4,4-tetramethyl-chroman:

A solution of 4-bromo-2-(3-hydroxy-1,1,3-trimethyl-butyl)-phenol (1.1 g,3.92 mmol) and p-toluene sulfonic acid (0.744 g, 3.92 mmol) in benzene(20 mL) was refluxed overnight. The reaction mixture cooled to ambienttemperature, filtered on silica gel and washed with 10% ethyl acetate inhexane. The filtrate and washings were evaporated in vacuo to an oilwhich was subjected to flash column chromatography over silica gel(230-400 mesh) using 5% ethyl acetate in hexane as the eluent to affordthe title compound as a pale yellow oil (0.84 g, 80%).

¹H-NMR (300 MHz, CDCl₃):δ 1.34(s, 6H), 1.35(s, 6H), 1.82(s, 2H), 6.68(d,J=8.4 Hz, 1H), 7.16(dd, J=2.7, 8.7 Hz, 1H), 7.37(d, J=2.6 Hz, 1H).

The synthesis of this compound, as described here, is in close analogyto the synthesis of 6-bromo-2,2,4,4-tetramethylthiochroman, as describedin U.S. Pat. No. 5,045,551

2,2,4,4-tetramethyl-6-(2-trimethylsilyl)ethynyl chroman:

Following general procedure D and using 6-bromo-2,2,4,4-tetramethylchroman (0.5 g, 1.87 mmol), triethyl amine (5 mL), anhydroustetrahydrofuran (15 mL),copper(I)iodide (0.107 g, 0.156 mmol),trimethylsilyl acetylene (1.84 g, 18.7 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.39 g, 0.56 mmol) thetitle compound was obtained as a brown oil (0.61 g, 100%).

¹H NMR (300 MHz, CDCl₃): δ 7.43 (d, 1H, J=2.1 Hz), 7.23 (dd, 1H, J=7.9,2.1 Hz), 6.73 (d, 1H, J=8.2 Hz), 1.83 (s, 2H), 1.36 (s, 12H), 0.28 (s,9H).

6-Ethynyl-2,2,4,4-tetramethyl chroman:

Following general procedure E and using2,2,4,4-tetramethyl-6-(2-trimethylsilyl)ethynyl chroman (0.61 g, 1.87mmol), potassium carbonate (1.9 g, 13.74 mmol) and methanol the titlecompound was obtained (0.4 g, 90%).

¹H NMR (300 MHz, CDCl₃): δ 7.47 (d, 1H, J=2.1 Hz), 7.24 (dd, 1H, J=7.9,2.1 Hz), 6.76 (d, 1H, J=8.2 Hz), 3.01 (s, 1H), 1.85 (s, 2H), 1.37 (s,6H), 1.36 (s, 6H).

An alternative synthesis for this compound is described in U.S. Pat.Nos. 5,045,551 and 5,616,597

General Procedure M: 6-Bromo-2,2,4,4-tetramethyl-chroman-8-carbaldehyde(Intermediate 30)

A stirred, cooled (ice bath) solution of 6-bromo-2,2,4,4-tetramethylchroman, (0.5 g, 1.865 mmol) in anhydrous dichloromethane (5 mL) wastreated with a 1M solution (1.86 mL, 1.86 mmol) of titaniumtetrachloride in dichloromethane followed by α,α-dichloro methyl ether(0.214 g, 1.865 mmol). The reaction mixture was allowed to warm toambient temperature for 4 h. The reaction mixture was diluted withdiethyl ether, washed with brine (×1) and dried over anhydrous sodiumsulfate, filtered and evaporated in vacuo to a residue which wassubjected to flash column chromatography over silica gel (230-400 mesh)using 5% ethyl acetate in hexane to afford the title compound as ayellow solid (0.52 g, 94%).

¹H NMR (300 MHz, CDCl₃): δ 10.38 (s, 1H), 7.72 (d, 1H, J=2.6 Hz), 7.57(d, 1H, J=2.6 Hz), 1.88 (s, 2H), 1.41 (s, 6H), 1.36 (s, 6H).

General Procedure N: 6-Bromo-8-vinyl -2,2,4,4-tetramethyl-chroman(Intermediate 31)

A solution of methylidene triphenyl phosphorane [generated from methyltriphenylphosphonium bromide (7 g, 20 mmol) and (11.8 mL, 19 mmol) of a1.6M solution of n-butyl lithium in hexanes] was added6-bromo-2,2,4,4-tetramethyl chroman-8-carbaldehyde (Intermediate 30,0.52 g, 1.75 mmol). After 1 h the reaction mixture was diluted withhexane, washed with brine (×1), dried over anhydrous sodium sulfate,filtered and evaporated in vacuo to a clear oil which was subjected toflash column chromatography over silica gel (230-400 mesh) using 2%ethyl acetate in hexane as the eluent to afford the title compound as aclear oil (0.37 g, 72%).

¹H NMR (300 MHz, CDCl₃): δ 7.46 (d, 1H, J=2.5 Hz), 7.33 (d, 1H, J=2.5Hz), 7.03 (dd, 1H, J=11.3, 17.9 Hz), 5.75 (dd, 1H, J=1.4, 17.9 Hz), 5.30(dd, 1H, J=1.4, 11.3 Hz), 1.85 (s, 2H), 1.39 (s, 6H), 1.37 (s, 6H).

General Procedure O: 6-Bromo-8-cyclopropyl-2,2,4,4-tetramethyl chroman(Intermediate 32)

A stirred, cooled (−30° C.) solution of6-bromo-8-vinyl-2,2,4,4-tetramethyl chroman (Intermediate 31, 0.37 g,1.26 mmol) in diethyl ether was treated with a solution of diazomethanein diethyl ether and catalytic amount of palladium (II)acetate (˜30 mg).The reaction mixture was allowed to warm to ambient temperature andsubjected to flash column chromatography over silica gel (230-400 mesh)using 2% ethyl acetate in hexane as the eluent to afford the titlecompound as a clear, pale yellow oil (0.376 g, 97%).

¹H NMR (300 MHz, CDCl₃): δ 7.17 (d, 1H, J=2.3 Hz), 6.73 (d, 1H, J=2.6Hz), 2.19-2.16 (m, 1H), 1.83 (s, 2H), 1.37 (s, 6H), 1.33 (s, 6H),0.94-0.88 (m, 2H), 0.64-0.59 (m, 2H).

8-Cyclopropyl-6-trimethylsilanylethynyl-2,2,4,4-tetramethyl chroman(Intermediate 33)

Following general procedure D and using6-bromo-8-cyclopropyl-2,2,4,4-tetramethyl chroman (Intermediate 32,0.376 g, 1.22 mmol), (trimethylsilyl)acetylene (4 mL, 28 mmol), triethylamine (3 mL), anhydrous tetrahydrofuran (5 mL), copper(I)iodide (0.025g, 0.13 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.075 g,0.11 mmol), the title compound was obtained as an oil (0.173 g, 43%).

¹H NMR (300 MHz, CDCl₃): δ 7.36 (d, 1H, J=2.2 Hz), 6.90 (d, 1H, J=1.9Hz), 2.31-2.22 (m, 1H), 1.96 (s, 2H), 1.49 (s, 6H), 1.46 (s, 6H),1.05-0.88 (m, 2H), 0.78-0.72 (m, 2H), 0.37 (s, 9H).

8-Cyclopropyl-6-ethynyl-2,2,4,4-tetramethyl chroman (Intermediate 34)

Following general procedure E and using8-cyclopropyl-6-trimethylsilanylethynyl-2,2,4,4-tetramethyl chroman(Intermediate 33, 0.17 g, 0.68 mmol), methanol and potassium carbonate(0.2 g, 1.47 mmol) the title compound was obtained as an oil (0.064 g,47%).

¹H NMR (300 MHz, CDCl₃): δ 7.38 (d, 1H, J=1.9 Hz), 6.92 (d, 1H, J=1.9Hz), 3.08 (s, 1H), 2.32-2.23 (m, 1H), 1.96 (s, 2H), 1.50 (s, 6H), 1.46(s, 6H), 1.05-0.99 (m, 2H), 0.77-0.72 (m, 2H).

4-(8-Cyclopropyl-2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)-benzoic acidethyl ester (Compound 33, General Formula 8)

Following general procedure F and using8-cyclopropyl-6-ethynyl-2,2,4,4-tetramethylchroman (Intermediate 34, 0.1g, 0.38 mmol), ethyl-4-iodo-benzoate (Reagent A, 0.1 g, 0.34 mmol),triethyl amine (5 mL), tetrahydrofuran(10 mL), copper(I)iodide(0.025 g,0.13 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.075 g,0.11 mmol) followed by flash column chromatography over silica gel(230-400 mesh) using 5-10% ethyl acetate in hexane as the eluent, thetitle compound was obtained (0.135 g, 89%).

¹H NMR (300 MHz, CDCl₃): δ 8.00 (d, 2H, J=8.2 Hz), 7.55 (d, 2H, J=8.2Hz), 7.30 (d, 1H, J=1.8 Hz), 6.84 (d, 1H, J=2.0 Hz), 4.38 (q, 2H, J=6.9Hz), 2.22-2.12 (m, 1H), 1.85 (s, 2H), 1.40 (t, 3H, J=6.9 Hz), 1.38 (s,6H), 1.36 (s, 6H), 0.92-0.88 (m, 2H), 0.67-0.62 (m, 2H).

4-(8-Cyclopropyl-2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)-benzoic acid(Compound 34, General Formula 8)

Following general procedure L and using4-(8-cyclopropyl-2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)-benzoic acidethyl ester (Compound 33, 0.133 g, 0.34 mmol), 5 mL of methanol and 1Msodium hydroxide solution (2 mL) followed by preparative reverse phaseHPLC using 10% water in acetonitrile as the mobile phase, the titlecompound was obtained as a solid (0.093 g, 73%).

¹H NMR (300 MHz, CDCl₃): δ 11.26 (br s, 1H), 8.08 (d, 2H, J=8.2 Hz),7.59 (d, 2H, J=8.2 Hz), 7.31 (d, 1H, J=1.8 Hz), 6.85 (d, 1H, J=2.1 Hz),2.22-2.13 (m, 1H), 1.85 (s, 2H), 1.38 (s, 6H), 1.36 (s, 6H), 0.95-0.87(m, 2H), 0.68-0.63 (m, 2H).

[4-(8-Cyclopropyl-2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)phenyl]acetic acid methyl ester (Compound 35, General Formula 8)

Following general procedure F and using8-cyclopropyl-6-ethynyl-2,2,4,4-tetramethylchroman (Intermediate 34,0.096 g, 0.38 mmol), methyl-4-iodo phenyl acetate (Reagent B, 0.094 g,0.34 mmol), triethyl amine (3 mL), tetrahydrofuran (3 mL),copper(I)iodide (0.025 g, 0.13 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.075 g, 0.11 mmol) thetitle compound was obtained (0.137 g, 90%). ¹H NMR (300 MHz, CDCl₃): δ7.47 (d, 2H, J=7.9 Hz), 7.29 (d, 1H, J=1.8 Hz), 7.24 (d, 2H, J=7.9 Hz),6.82 (d, 1H, J=2.1 Hz), 3.70 (s, 3H), 3.63 (s, 2H), 2.22-2.13 (m, 1H),1.85 (s, 2H), 1.38 (s, 6H), 1.36 (s, 6H), 0.94-0.86 (m, 2H), 0.68-0.63(m, 2H).

[4-(8-Cyclopropyl-2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)phenyl]acetic acid (Compound 36, General Formula 8)

Following general procedure L and using[4-(8-cyclopropyl-2,2,4,4-tetramethyl-chroman-6-ylethynyl) phenyl]acetic acid methyl ester (Compound 35, 0.137 g, 0.30 mmol), 5 mL ofmethanol and 1M sodium hydroxide solution (2 mL) followed by preparativereverse phase HPLC using 10% water in acetonitrile as the mobile phase,the title compound was obtained as a solid (0.11 g, 80%).

¹H NMR (300 MHz, CDCl₃): δ 11.56 (br s, 1H), 7.47 (d, 2H, J=8.9 Hz),7.28 (d, 1H, J=1.9 Hz), 7.23 (d, 2H, J=8.5 Hz), 6.82 (d, 1H, J=1.9 Hz),3.62 (s, 2H), 2.21-2.12 (m, 1H), 1.83 (s, 2H), 1.36 (s, 6H), 1.34 (s,6H), 0.93-0.82 (m, 2H), 0.72-0.62 (m, 2H).

[4-(8-Cyclopropyl-2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)-2-fluorophenyl]acetic acid ethyl ester (Compound 37, General Formula 8)

Following general procedure F and using8-cyclopropyl-6-ethynyl-2,2,4,4-tetramethylchroman (Intermediate 34,0.096 g, 0.38 mmol), ethyl-2-fluoro-4-iodo phenyl acetate (Reagent C,0.104 g, 0.34 mmol), triethyl amine (3 mL), tetrahydrofuran (3 mL),copper(I)iodide (0.020 g, 0.11 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.060 g, 0.085 mmol) thetitle compound was obtained (0.14 g, 85%).

¹H NMR (300 MHz, CDCl₃): δ 7.31 (d, 1H, J=1.9 Hz), 7.29-7.21 (m, 3H),6.85 (d, 1H, J=1.9 Hz), 4.20 (q, 2H, J=7.1 Hz), 3.68 (s, 2H), 2.24-2.14(m, 1H), 1.87 (s, 2H), 1.40 (s, 6H), 1.38 (s, 6H), 1.28 (t, 3H, J=7.1Hz), 0.96-0.85 (m, 2H), 0.70-0.64 (m, 2H).

[4-(8-Cyclopropyl-2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)-2-fluorophenyl]acetic acid (Compound 38, General Formula 8)

Following general procedure L and using[4-(8-cyclopropyl-2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)-2-fluorophenyl]acetic acid ethyl ester (Compound 37, 0.14 g, 0.323 mmol), 5 mL ofmethanol and 1M sodium hydroxide solution (2 mL) followed by reversephase HPLC using 10% water in acetonitrile as the mobile phase, thetitle compound was obtained as a solid (0.110 g, 80%).

¹H NMR (300 MHz, CDCl₃): δ 7.28 (d, 1H, J=2.1 Hz), 7.27-7.17 (m, 3H),6.82 (d, 1H, J=1.8 Hz), 3.70 (s, 2H), 2.21-2.11 (m, 1H), 1.84 (s, 2H),1.37 (s, 6H), 1.35 (s, 6H), 0.94-0.87 (m, 2H), 0.67-0.62 (m, 2H).

General Procedure P: 6-Bromo-4,4-dimethyl-2-methylene chroman(Intermediate 35)

A stirred, cooled (ice bath) solution of6-bromo-4,4-dimethyl-chroman-2-one available in accordance with U.S.Pat. No. 5,399,561 incorporated herein by reference (1 g, 3.92 mmol) in8 mL of anhydrous tetrahydrofuran was treated with a 0.5 M solution ofμ-chloro-μ-methylene-[bis(cyclopentadienyl)titanium]dimethylaluminum(Tebbe reagent) in toluene (8.23 mL, 4.12 mmol). After 10 minutes, thereaction mixture was poured into ice-water mixture containing 50 mL of1M sodium hydroxide and extracted with hexane. The hexane extract waswashed with brine (×1), filtered over a bed of celite and evaporated invacuo to an oil which was subjected to flash column chromatography oversilica gel (230-400 mesh) using hexane as the eluent to afford the titlecompound (0.74 g, 74%) as a clear oil.

¹H NMR (300 MHz, CDCl₃): δ 7.34 (d, 1H, J=2.3 Hz), 7.23 (dd, 1H,J=2.3,8.5 Hz), 6.77 (d, 1H, J=8.0 Hz), 4.61 (d, 1H, J=0.73 Hz), 4.17 (d,1H, J=0.73 Hz), 2.33 (s, 2H), 1.27 (s, 6H).

General Procedure Q:6-Bromo-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 36)

A solution of diethyl zinc in hexane (1M, 7.1 mL) was treated withdiiodomethane (1.89 g, 7.1 mmol). After 5 minutes, a solution of6-bromo-4,4-dimethyl-2-methylene chroman (Intermediate 35, 0.44 g, 1.77mmol) in 3 mL of hexane was added and the solution was refluxed for 1 h.The reaction mixture was then cooled to ambient temperature, dilutedwith hexane, washed with brine (×1), dried over anhydrous sodiumsulfate, filtered and evaporated in vacuo to a residue which wassubjected to flash column chromatography over silica gel (230-400 mesh)using hexane as the eluent to obtain the title compound (0.44 g, 93%).

¹H NMR (300 MHz, CDCl₃): δ 7.47 (d, 1H, J=2.3 Hz), 7.23 (dd, 1H,J=2.3,8.5 Hz), 6.70 (d, 1H, J=8.0 Hz), 1.96 (s, 2H), 1.47 (s, 6H),1.09-1.05 (m, 2H), 0.74-0.70 (m, 2H).

3,4-Dihydro-4,4-dimethyl-6-(trimethylsilanyl)ethynylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 37)

Following general procedure D and using6-bromo-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 36, 0.44 g, 1.65 mmol), triethyl amine (4 mL), anhydroustetrahydrofuran (5 mL), copper(I)iodide (0.95 g, 0.5 mmol),trimethylsilyl acetylene (1.62 g, 16.5 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.4 g, 0.56 mmol), thetitle compound was obtained as a brown oil (0.4 g, 86%).

¹H NMR (300 MHz, CDCl₃): δ 7.44 (d, 1H, J=2.1 Hz), 7.18 (dd, 1H,J=2.1,8.5 Hz), 6.65 (d, 1H, J=8.5 Hz), 1.87 (s, 2H), 1.37 (s, 6H),1.01-0.97 (m, 2H), 0.65-0.61 (m, 2H), 0.26 (s, 9H).

6-Ethynyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 38)

Following general procedure E and using3,4-dihydro-4,4-dimethyl-6-(trimethylsilanyl)ethynylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 37, 0.4 g, 1.42 mmol), potassium carbonate (0.98 g, 7.1mmol) and methanol, the title compound was obtained as a yellow oil (0.3g, 100%).

¹H NMR (300 MHz, CDCl₃): δ 7.44 (d, 1H, J=2.1 Hz), 7.18 (dd, 1H, J=2.1,8.5 Hz), 6.65 (d, 1H, J=8.5 Hz), 2.97 (s, 1H), 1.86 (s, 2H), 1.37 (s,6H), 1.00-0.95 (m, 2H), 0.64-0.59 (m, 2H).

Benzoic acid,4-[(3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-ethylester (Compound 39, General Formula 1)

Following general procedure F and using6-ethynyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 38, 0.06 g, 0.28 mmol), ethyl-4-iodo-benzoate (Reagent A,0.086 g, 0.31 mmol), triethyl amine (4 mL), tetrahydrofuran(4 mL),copper(I)iodide(0.032 g, 0.17 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.118 g, 0.17 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using 5-10% ethyl acetate in hexane as the eluent, the title compoundwas obtained (0.07 g, 70%).

¹H NMR (300 MHz, CDCl₃): δ 8.01 (d, 2H, J=8.2 Hz), 7.56 (d, 2H, J=8.5Hz), 7.49 (d, 1H, J=2.1 Hz), 7.24 (dd, 1H, J=2.1,8.5 Hz), 6.70 (d, 1H,J=8.5 Hz), 4.38 (q, 2H, J=7.1 Hz), 1.89 (s, 2H), 1.40 (s, 6H), 1.40 (t,3H, J=7.0 Hz), 1.02-0.98 (m, 2H), 0.67-0.62 (m, 2H).

Benzoic acid,4-[(3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-(Compound 40, General Formula 1)

Following general procedure L and using benzoic acid,4-[(3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-ethylester (Compound 39, 0.07 g, 0.196 mmol), 5 mL of ethanol and 1M sodiumhydroxide solution (2 mL) followed by preparative reverse phase HPLCusing 10% water in acetonitrile as the mobile phase, the title compoundwas obtained as a solid (0.034 g, 52%).

¹H NMR (300 MHz, CD₃COCD₃): δ 8.05 (d, 2H, J=8.2 Hz), 7.64 (d, 2H, J=8.2Hz), 7.60 (d, 1H, J=2.1 Hz), 7.28 (dd, 1H, J=2.1, 8.5 Hz), 6.73 (d, 1H,J=8.5 Hz), 1.95 (s, 2H), 1.43 (s, 6H), 0.96-0.92 (m, 2H), 0.74-0.71 (m,2H).

Benzeneacetic acid,4-[(3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-methylester (Compound 41, General Formula 1)

Following general procedure F and using6-ethynyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 38, 0.060 g, 0.28 mmol), methyl-4-iodo phenyl acetate(Reagent B, 0.078 g, 0.28 mmol), triethyl amine (4 mL), tetrahydrofuran(4 mL), copper(I)iodide (0.032 g, 0.17 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.118 g, 0.17 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using 5% ethyl acetate in hexane as the eluent, the title compound wasobtained (0.084 g, 84%).

¹H NMR (300 MHz, CDCl₃): δ 7.48-7.45 (m, 3H), 7.26-7.20 (m, 3H), 6.67(d, 1H, J=8.5 Hz), 3.70 (s, 3H), 3.63 (s, 2H), 1.89 (s, 2H), 1.40 (s,3H), 1.40 (s, 3H), 1.01-0.97 (m, 2H), 0.67-0.61 (m, 2H).

Benzeneacetic acid,4-[(3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-(Compound 42, General Formula 1)

A solution of benzeneacetic acid,4-[(3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-methylester (Compound 41, 0.084 g, 0.24 mmol) in 5 mL of methanol was treatedwith 1M sodium hydroxide solution (2 mL) and heated at 55° C. for 2 h.The volatiles were distilled off in vacuo and the residue was acidifiedwith 10% hydrochloric acid and extracted with ethyl acetate (×2). Thecombined organic phase was washed with brine (×1), dried over anhydroussodium sulfate, filtered and evaporated in vacuo to a residue which waspurified by preparative reverse phase HPLC using 10% water inacetonitrile as the mobile phase to afford the title compound (0.080 g,100%).

¹H NMR (300 MHz, CD₃COCD₃): δ 7.49-7.46 (m, 3H), 7.25 (d, 2H, J=8.2 Hz),7.22 (dd, 1H, J=2.1,8.5 Hz), 6.68 (d, 1H, J=8.5 Hz), 3.66 (s, 2H), 1.88(s, 2H), 1.44 (s, 6H), 1.01-0.97 (m, 2H), 0.67-0.61 (m, 2H).

2-Fluoro-benzoic acid,4-[(3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]methylester (Compound 43, General Formula 1)

Following general procedure F and6-ethynyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 38, 0.050 g, 0.23 mmol), methyl-2-fluoro-4-iodo-benzoate(Reagent G, 0.069 g, 0.24 mmol), triethyl amine (5 mL),tetrahydrofuran(5 mL), copper(I)iodide(0.013 g, 0.07 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.049 g, 0.07 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using 5-10% ethyl acetate in hexane as the eluent, the title compoundwas obtained (0.080 g, 100%).

¹H NMR (300 MHz, CDCl₃): δ 7.90 (t, 1H, J=7.9 Hz), 7.63 (d, 1H, J=1.8Hz), 7.32 (dd, 1H, J=1.5, 8.2 Hz), 7.26 (dd, 1H, J=1.5,11.4 Hz), 7.24(dd, 1H, J=2.1, 8.5 Hz), 6.71 (d, 1H, J=8.5 Hz), 1.97 (s, 2H), 1.44 (s,6H), 0.98-0.94 (m, 2H), 0.76-0.71 (m, 2H).

2-Fluoro-benzoic acid,4-[(3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-(Compound 44, General Formula 1)

Following general procedure L and using 2-fluoro-benzoic acid,4-[(3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-methylester (Compound 43, 0.08 g, 0.23 mmol), 5 mL of methanol and 2M sodiumhydroxide solution (1 mL) followed by flash column chromatography oversilica gel (230-400 mesh) using ethyl acetate as the eluent, the titlecompound was obtained (0.020 g, 25%).

¹H NMR (300 MHz, CD₃COCD₃): δ 7.99 (t, 1H, J=7.9 Hz), 7.63 (d, 1H, J=2.1Hz), 7.44 (dd, 1H, J=1.5, 7.9 Hz), 7.37 (dd, 1H, J=1.5, 11.4 Hz), 7.31(dd, 1H, J=2.1, 8.5 Hz), 6.75 (d, 1H, J=8.2 Hz), 1.97 (s, 2H), 1.44 (s,6H), 0.98-0.94 (m, 2H), 0.76-0.71 (m, 2H).

General Procedure R: 2,2,4,4-Tetramethyl-chroman-6-carboxylic acid(Intermediate 39)

A stirred, cooled (−78° C.) solution of 6-bromo-2,2,4,4-tetramethylchroman (1.2 g, 4.47 mmol) in 15 mL of anhydrous tetrahydrofuran wastreated with a 1.7M solution of tert-butyl lithium solution in pentane (5.27 mL, 8.9 mmol). After 10 minutes at −78° C., carbon dioxide(generated from dry ice) was bubbled into the reaction mixture. Thereaction mixture was allowed to warm to ambient temperature. Thereaction mixture was diluted with ethyl acetate, washed with brine,dried over anhydrous sodium sulfate, filtered and evaporated in vacuo toa residue which was subjected to flash column chromatography over silicagel (230-400 mesh) using ethyl acetate as the eluent to afford the titlecompound as a white solid (1.1 g, 92%).

¹H NMR (300 MHz, CDCl₃): δ 12.17 (br s, 1H), 8.09 (d, 1H, J=2.1 Hz),7.85 (dd, 1H, J=2.1, 8.5 Hz), 6.83 (d, 1H, J=8.2 Hz), 1.87 (s, 2H), 1.39(s, 6H), 1.37 (s, 6H).

2,2,4,4-Tetramethyl-chroman-6-carboxylic acid4-(tert-butoxycarbonylmethyl)phenyl ester (Compound 45, General Formula8)

A solution of 2,2,4,4-tetramethyl chroman-6-carboxylic acid (0.1 g, 0.43mmol) in thionyl chloride (10 mL) was refluxed for 2 h. The thionylchloride was evaporated under reduced pressure and the residue wasdissolved in 5 mL of dichloromethane and treated with triethyl amine (5mL) followed by tert-butyl-4-hydroxy phenyl acetate (Reagent E, 0.088 g,0.427 mmol). After 0.5 h, the reaction mixture was subjected to flashcolumn chromatography over silica gel (230-400 mesh) using 5-10% ethylacetate in hexane as the eluent to afford the title compound (0.1 g,55%).

¹H NMR (300 MHz, CDCl₃): δ 8.15 (d, 1H, J=2.1 Hz), 7.93 (dd, 1H, J=2.1,8.5 Hz), 7.33 (d, 2H, J=8.8 Hz), 7.16 (d, 2H, J=8.8 Hz), 6.88 (d, 1H,J=8.5 Hz), 3.54 (s, 2H), 1.89 (s, 2H), 1.45 (s, 9H), 1.41 (s, 6H), 1.40(s, 6H).

2,2,4,4-Tetramethyl-chroman-6-carboxylic acid 4-(carboxymethyl)phenylester (Compound 46, General Formula 8)

A solution of 2,2,4,4-tetramethyl-chroman-6-carboxylic acid4-(tert-butoxycarbonylmethyl)phenyl ester (Compound 45, 0.1 g, 0.23mmol) was treated with 5 mL of trifluoroacetic acid and stirred atambient temperature for 1 h. The trifluoroacetic acid was distilled offunder reduced pressure and the residue was subjected to preparativereverse phase HPLC using 10% water in acetonitrile as the mobile phaseto afford the title compound as a white solid (0.045 g, 50%).

¹H NMR (300 MHz, CDCl₃): δ 8.13 (d, 1H, J=2.1 Hz), 7.92 (dd, 1H, J=2.3,8.5 Hz), 7.35 (d, 2H, J=8.8 Hz), 7.17 (d, 2H, J=8.5 Hz), 6.87 (d, 1H,J=8.5 Hz), 3.68 (s, 2H), 1.89 (s, 2H), 1.41 (s, 6H), 1.39 (s, 6H).

6-Bromo-8-carbaldehyde-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 40)

Following general procedure M and using6-bromo-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate36, 2.3 g, 8.65 mmol), anhydrous dichloromethane (25 mL), 1M solution(8.65 mL, 8.65 mmol) of titanium tetrachloride in dichloromethane andα,α-dichloro methyl ether (1.09 g, 9.52 mmol) followed by flash columnchromatography using 10% ethyl acetate in hexane as the eluent, thetitle compound was obtained as a yellow solid (2.06 g, 81%).

¹H NMR (300 MHz, CDCl₃): δ 10.20 (s, 1H), 7.69 (d, 1H, J=2.6 Hz), 7.58(d, 1H, J=2.6 Hz), 1.92 (s, 2H), 1.40 (s, 6H), 1.09-1.04 (m, 2H),0.73-0.69 (m, 2H).

6-Bromo-3,4-dihydro-4,4-dimethyl-8-vinylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 41)

Following general procedure N and using A solution of methylidenetriphenyl phosphorane [generated from methyl triphenylphosphoniumbromide (7 g, 20 mmol) and 1.6M solution of n-butyl lithium in hexanes(11.8 mL, 19 mmol)],6-bromo-8-carbonyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate40, 2.06 g, 7 mmol) followed by flash column chromatography over silicagel (230-400 mesh) using 1-2% ethyl acetate in hexane as the eluent, thetitle compound was obtained as a clear oil (1.36 g, 66%).

¹H NMR (300 MHz, CDCl₃): δ 7.36 (d, 1H, J=2.3 Hz), 7.28 (d, 1H, J=2.6Hz), 6.80 (dd, 1H, J=11.1, 17.9 Hz), 5.63 (dd, 1H, J=1.2, 17.9 Hz), 5.19(dd, 1H, J=1.2, 11.1 Hz), 1.84 (s, 2H), 1.35 (s, 6H), 0.97 (t, 2H, J=6.3Hz), 0.62 (d, 1H, J=5.3 Hz), 0.60 (d, 1H, J=6.2 Hz).

6-Bromo-8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 42)

Following general procedure O and using A6-bromo-3,4-dihydro-4,4-dimethyl-8-vinylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 41, 1.36 g, 4.6 mmol), a solution of diazomethane indiethyl ether and palladium (II)acetate (˜30 mg) followed by flashcolumn chromatography over silica gel (230-400 mesh) using hexane as theeluent, the title compound was obtained as a clear oil (1.38 g, 100%).

¹H NMR (300 MHz, CDCl₃): δ 7.19 (d, 1H, J=2.2 Hz), 6.71 (d, 1H, J=2.2Hz), 1.99-1.92 (m, 1H), 1.87 (s, 2H), 1.35 (s, 6H), 1.00-0.95 (m, 2H)0.90-0.82 (m, 2H), 0.65-0.54 (m, 4H).

8-Cyclopropyl-3,4-dihydro-4,4-dimethyl-6-(trimethylsilanyl)ethynylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 43)

Following general procedure D and6-bromo-8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 42, 0.74 g, 2.4 mmol), (trimethylsilyl)acetylene (4 mL, 28mmol), triethyl amine (8 mL), anhydrous tetrahydrofuran, copper(I)iodide(0.050 g, 0.26 mmol) and dichlorobis(triphenylphosphine)palladium(II)(0.15 g, 0.22 mmol), followed by flash column chromatography over silicagel (230-400 mesh) using 1-2% ethyl acetate in hexane as the eluent, thetitle compound was obtained as an oil (0.62 g, 80%).

¹H NMR (300 MHz, CDCl₃): δ 7.28 (d, 1H, J=1.9 Hz), 6.77 (d, 1H, J=1.9Hz), 2.03-1.94 (m, 1H), 1.91 (s, 2H), 1.40 (s, 6H), 1.05-0.98 (m, 2H)0.95-0.83 (m, 2H), 0.69-0.59 (m,4H), 0.27 (s, 9H).

8-Cyclopropyl-6-ethynyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 44)

Following general procedure E, and8-cyclopropyl-3,4-dihydro-4,4-dimethyl-6-(trimethylsilanyl)ethynylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 43, 0.62 g, 1.9 mmol), methanol and potassium carbonate(0.5 g, 3.6 mmol) followed by flash column chromatography over silicagel (230-400 mesh) using 1-2% ethyl acetate in hexane as the eluent, thetitle compound was obtained as an oil (0.5 g, 100%).

¹H NMR (300 MHz, CDCl₃): δ 7.30 (d, 1H, J=1.8 Hz), 6.80 (d, 1H, J=2.0Hz), 2.97 (s, 1H), 2.04-1.95 (m, 1H), 1.91 (s, 2H), 1.39 (s, 6H),1.20-0.90 (m, 2H), 0.90-0.84 (m, 2H), 0.75-0.58 (m, 4H).

Benzeneacetic acid,4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6yl)ethynyl]-methylester (Compound 47, General Formula 1)

Following general procedure F and using8-cyclopropyl-6-ethynyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 44, 0.11 g, 0.43 mmol), methyl-4-iodo phenyl acetate(Reagent B, 0.11 g, 0.41 mmol), triethyl amine (5 mL), tetrahydrofuran(3 mL), copper(I)iodide (0.025 g, 0.13 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.075 g, 0.11 mmol), thetitle compound was obtained as a clear oil (0.096 g, 56%).

¹H NMR (300 MHz, CDCl₃): δ 7.46 (d, 2H, J=8.0 Hz), 7.31 (d, 1H, J=1.9Hz), 7.24 (d, 2H, J=8.2 Hz), 6.81 (d, 1H, J=1.9 Hz), 3.69 (s, 3H), 3.62(s, 2H), 2.04-1.95 (m, 1H), 1.90 (s, 2H), 1.39 (s, 6H), 1.03-0.99 (m,2H), 0.90-0.83 (m, 2H), 0.68-0.59 (m, 4H).

Benzeneacetic acid,4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-(Compound 48, General Formula 1)

Following general procedure L and using benzeneacetic acid,4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-methylester (Compound 47, 0.96 g, 0.24 mmol), 5 mL of methanol and 1M sodiumhydroxide solution (2 mL) followed by flash column chromatography oversilica gel (230-400 mesh) using 15% methanol in dichloromethane as theeluent, the title compound was obtained as a solid (0.084 g, 91%).

¹H NMR (300 MHz, CDCl₃): δ 10.27 (br s, 1H), 7.46 (d, 2H, J=8.2 Hz),7.30 (d, 1H, J=1.8 Hz), 7.23 (d, 2H, J=8.2 Hz), 6.80 (d, 1H, J=1.5 Hz),3.63 (s, 2H), 2.07-1.94 (m, 1H), 1.89 (s, 2H), 1.39 (s, 6H), 1.03-0.98(m, 2H), 0.89-0.82 (m, 2H), 0.73-0.59 (m, 4H).

4-[(8-Cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-2-fluoro-benzeneaceticacid methyl ester (Compound 49, General Formula 1)

Following general procedure F and using8-cyclopropyl-6-ethynyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 44, 0.125 g, 0.5 mmol), methyl-2-fluoro-4-iodo phenylacetate (Reagent H, 0.14 g, 0.5 mmol), triethyl amine (3 mL),tetrahydrofuran (3 mL), copper(I)iodide (0.020 g, 0.1 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.060 g, 0.085 mmol)followed by preparative normal phase HPLC using 10% ethyl acetate inhexane as the mobile phase, the title compound was obtained (0.096 g,46%).

¹H NMR (300 MHz, CDCl₃): δ 7.30 (d, 1H, J=2.1 Hz), 7.26-7.18 (m, 3H),6.80 (d, 1H, J=1.8 Hz), 3.71 (s, 3H), 3.67 (s, 2H), 2.04-1.94 (m, 1H),1.90 (s, 2H), 1.40 (s, 6H), 1.18-0.99 (m, 2H), 0.90-0.83 (m, 2H),0.68-0.59 (m, 4H).

4-[(8-Cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-2-fluoro-benzeneaceticacid (Compound 50, General Formula 1)

Following general procedure L and using4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-2-fluoro-benzeneaceticacid methyl ester (Compound 49, 0.096 g, 0.23 mmol), 5 mL of methanoland 1M sodium hydroxide solution (2 mL) followed by flash columnchromatography over silica gel (230-400 mesh) using 15% methanol indichloromethane as the eluent, the title compound was obtained as asolid (0.093 g, 100%).

¹H NMR (300 MHz, CDCl₃): δ 9.50 (br s, 1H), 7.27 (d, 1H, J=2.1 Hz),7.24-7.15 (m, 3H), 6.77 (d, 1H, J=1.5 Hz), 3.67 (s, 2H), 2.01-1.91 (m,1H), 1.87 (s, 2H), 1.36 (s, 6H), 1.01-0.96 (m, 2H), 0.87-0.80 (m, 2H),0.65-0.56 (m, 4H).

Benzoic acid,4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-ethylester (Compound 51, General Formula 1)

Following general procedure F and using8-cyclopropyl-6-ethynyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 44, 0.05 g, 0.2 mmol), ethyl-4-iodo-benzoate (Reagent A,0.055 g, 0.2 mmol), triethyl amine (3 mL), tetrahydrofuran(3 mL),copper(I)iodide(0.020 g, 0.1 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.060 g, 0.085 mmol), thetitle compound was obtained (0.06 g, 75%).

¹H NMR (300 MHz, CDCl₃): δ 8.00 (d, 2H, J=8.2 Hz), 7.55 (d, 2H, J=8.2Hz), 7.33 (d, 1H, J=1.8 Hz), 6.83 (d, 1H, J=2.1 Hz), 4.38 (q, 2H, J=7.1Hz), 2.04-1.95 (m, 1H), 1.91 (s, 2H), 1.40 (s, 6H), 1.40 (t, 3H, J=7.0Hz), 1.05-0.95 (m, 2H), 0.91-0.84 (m, 2H), 0.69-0.61 (m, 4H).

Benzoic acid,4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-(Compound 52, General Formula 1)

Following general procedure L and using benzoic acid,4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-ethylester (Compound 51, 0.06 g, 0.15 mmol), 5 mL of methanol and 1M sodiumhydroxide solution (2 mL) followed by preparative reverse phase HPLCusing 10% water in acetonitrile as the mobile phase, the title compoundwas obtained as a solid (0.040 g, 72%).

¹H NMR (300 MHz, CDCl₃): δ 8.08 (d, 2H, J=8.8 Hz), 7.60 (d, 2H, J=8.8Hz), 7.34 (d, 1H, J=1.9 Hz), 6.84 (d, 1H, J=1.9 Hz), 2.05-1.96 (m, 1H),1.92 (s, 2H), 1.41 (s, 6H), 1.05-0.95 (m, 2H), 0.92-0.83 (m, 2H),0.75-0.60 (m, 4H).

4-[(8-Cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-2-fluoro-benzoicacid methyl ester (Compound 53, General Formula 1)

Following general procedure F and using8-cyclopropyl-6-ethynyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 44, 0.03 g, 0.11 mmol), methyl-2-fluoro-4-iodo-benzoate(Reagent G, 0.025 g, 0.09 mmol), triethyl amine (3 mL),tetrahydrofuran(3 mL), copper(I)iodide(0.020 g, 0.1 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.06 g, 0.085 mmol)followed by preparative normal phase HPLC using 10% ethyl acetate inhexane as the mobile phase, the title compound was obtained as a whitesolid (0.019 g, 40%).

¹H NMR (300 MHz, CDCl₃): δ 7.97 (t, 1H, J=7.8 Hz), 7.34 (d, 1H, J=1.9Hz), 7.32-7.25 (m, 2H), 6.83 (d, 1H, J=1.9 Hz), 3.95 (s, 3H), 2.06-1.96(m, 1H), 1.93 (s, 2H), 1.42 (s, 6H), 1.06-1.02 (m, 2H), 0.91-0.86 (m,2H), 0.71-0.61 (m, 4H).

4-[(8-Cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-2-fluoro-benzoicacid (Compound 54, General Formula 1)

Following general procedure L and using4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6yl)ethynyl]-2-fluoro-benzoicacid methyl ester (Compound 53, 0.01 g, 0.047 mmol), 5 mL of methanoland 1M sodium hydroxide solution (2 mL) followed by preparative reversephase HPLC using 10% water in acetonitrile as the mobile phase, thetitle compound was obtained as a solid (0.01 g, 56%).

¹H NMR (300 MHz, CDCl₃): δ 7.99 (t, 1H, J=8.0 Hz), 7.36-7.28 (m, 3H),6.83 (d, 1H, J=1.9 Hz), 2.18-1.95 (m, 1H), 1.92 (s, 2H), 1.41 (s, 6H),1.06-1.01 (m, 2H), 0.96-0.83 (m, 2H), 0.76-0.60 (m, 4H).

8-Acetyl-6-bromo-2,2,4,4-tetramethyl chroman (Intermediate 45)

A stirred, cooled (ice bath) suspension of aluminum chloride (0.99 g,7.46 mmol) in anhydrous dichloromethane (20 mL) was treated with acetylchloride (0.58 g, 7.46 mmol). After 5 minutes, a solution of6-bromo-2,2,4,4-tetramethyl chroman (1 g, 3.73 mmol)in dichloromethanewas added. The reaction was allowed to warm to ambient temperature andstirred for 2 h. The reaction mixture was then poured into icecontaining 10% hydrochloric acid and extracted with diethyl ether (×2).The combined organic phase was washed with saturated aqueous sodiumbicarbonate solution, dried over anhydrous sodium sulfate, filtered andevaporated in vacuo to a residue which was subjected to flash columnchromatography over silica gel (230-400 mesh) using 5% ethyl acetate inhexane as the eluent to afford the title compound as a pale yellow oil(0.95 g, 83%). It was used as such for the next step without anycharacterization.

6-Bromo-8-ethyl-2,2,4,4-tetramethyl chroman (Intermediate 46)

A stirred, cooled (ice bath) solution of8-acetyl-6-bromo-2,2,4,4-tetramethyl chroman (Intermediate 45, 0.95 g,3.1 mmol) in trifluoroacetic acid (10 mL) was treated withtriethylsilane (10 mL) and the resulting reaction mixture was allowed towarm to ambient temperature and stirred overnight. The volatiles weredistilled off in vacuo and the residue was diluted with water andextracted with hexane (×2). The combined organic phase was dried overanhydrous sodium sulfate, filtered and evaporated in vacuo to an oilwhich was subjected to flash column chromatography over silica gel(230-400 mesh) using hexane as the eluent to afford the title compoundas a clear oil, contaminated with a small amount to triethylsilane (0.51g, 56%).

¹H NMR (300 MHz, CDCl₃): δ 7.23 (d, 1H, J=2.3 Hz), 7.08 (d, 1H, J=2.3Hz), 2.58 (q, 2H, J=7.6 Hz), 1.81 (s, 2H), 1.34 (s, 6H), 1.33 (s, 6H),1.17 (t, 3H, J=7.6 Hz).

8-Ethyl-6-trimethylsilanylethynyl-2,2,4,4-tetramethyl chroman(Intermediate 47)

Following general procedure D and using6-bromo-8-ethyl-2,2,4,4-tetramethyl chroman (Intermediate 46, 0.5 g,1.61 mmol), (trimethylsilyl)acetylene (1.57 g, 16.1 mmol), triethylamine (8 mL), anhydrous tetrahydrofuran (10 mL), copper(I)iodide (0.025g, 0.13 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.075 g,0.11 mmol), followed by flash column chromatography over silica gel(230-400 mesh) using 5% ethyl acetate in hexane as the eluent, the titlecompound was obtained as an oil (0.137 g, 27%).

¹H NMR (300 MHz, CDCl₃): δ 7.27 (d, 1H, J=2.1 Hz), 7.10 (d, 1H, J=2.1Hz), 2.55 (q, 2H, J=7.6 Hz), 1.81 (s, 2H), 1.33 (s, 6H), 1.32 (s, 6H),1.15 (t, 3H, J=7.6 Hz), 0.24 (s, 9H).

8-Ethyl-6-ethynyl-2,2,4,4-tetramethyl chroman (Intermediate 48)

Following general procedure E and using8-ethyl-6-trimethylsilanylethynyl-2,2,4,4-tetramethyl chroman(Intermediate 47, 0.137 g, 0.44 mmol), methanol and potassium carbonate(0.1 g, 0.72 mmol) followed by flash column chromatography over silicagel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent, thetitle compound was obtained as an oil (0.066 g, 62%).

¹H NMR (300 MHz, CDCl₃): δ 7.33 (d, 1H, J=2.2 Hz), 7.15 (d, 1H, J=1.6Hz), 2.99 (s, 1H), 2.59 (q, 2H, J=7.6 Hz), 1.84 (s, 2H), 1.37 (s, 6H),1.35 (s, 6H), 1.19 (t, 3H, J=7.6 Hz).

[4-(8-Ethyl-2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)phenyl] acetic acidmethyl ester (Compound 55, General Formula 8)

Following general procedure F and using8-ethyl-6-ethynyl-2,2,4,4-tetramethylchroman (Intermediate 48, 0.033 g,0.136 mmol), methyl-4-iodo phenyl acetate (Reagent B, 0.034 g, 0.12mmol), triethyl amine (2 mL), tetrahydrofuran (2 mL), copper(I)iodide(0.025 g, 0.13 mmol) and dichlorobis(triphenylphosphine)palladium(II)(0.075 g, 0.11 mmol) the title compound was obtained (0.035 g, 73%).

¹H NMR (300 MHz, CDCl₃): δ 7.49 (d, 2H, J=7.9 Hz), 7.35 (d, 1H, J=1.8Hz), 7.26 (d, 2H, J=7.9 Hz), 7.18 (d, 1H, J=1.9 Hz), 3.72 (s, 3H), 3.65(s, 2H), 2.61 (q, 2H, J=7.5 Hz), 1.85 (s, 2H), 1.38 (s, 12H), 1.21 (t,3H, J=7.5 Hz).

[4-(8-Ethyl-2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)phenyl] acetic acid(Compound 56, General Formula 8)

Following general procedure L and using[4-(8-ethyl-2,2,4,4-tetramethyl-chroman-6-ylethynyl)phenyl] acetic acidmethyl ester (Compound 55, 0.035 g, 0.1 mmol), 5 mL of methanol and 1Msodium hydroxide solution (1 mL) followed by preparative reverse phaseHPLC using 10% water in acetonitrile as the mobile phase, the titlecompound was obtained as a solid (0.11 g, 25%).

¹H NMR (300 MHz, CDCl₃): δ 7.48 (d, 2H, J=8.0 Hz), 7.33 (d, 1H, J=1.9Hz), 7.25 (d, 2H, J=8.0 Hz), 7.15 (d, 1H, J=1.9 Hz), 3.65 (s, 2H), 2.59(q, 2H, J=7.5 Hz), 1.83 (s, 2H), 1.35 (s, 12H), 1.18 (t, 3H, J=7.4 Hz).

Spiro[2H-1-benzopyran-2,1′-cyclopropane]-6-carboxylic acid,8-cyclopropyl-3,4-dihydro-4,4-dimethyl- (Intermediate 49)

Following general procedure R and using6-bromo-8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 42, 0.45 g, 1.48 mmol), anhydrous tetrahydrofuran (5 mL),1.7M solution of tert-butyl lithium solution in pentane ( 1.74 mL, 2.96mmol) and carbon dioxide generated from dry ice, followed by flashcolumn chromatography over silica gel (230-400 mesh) using 50% ethylacetate in hexane as the eluent, the title compound was obtained as awhite solid (0.34 g, 85%).

¹H NMR (300 MHz, CDCl₃): δ 12.43 (br s, 1H), 7.94 (d, 1H, J=2.1 Hz),7.42 (d, 1H, J=1.8 Hz), 2.06-1.96 (m, 1H), 1.92 (s, 2H), 1.42 (s, 6H),1.12-0.97 (m, 2H), 0.95-0.81 (m, 2H), 0.77-0.60 (m, 4H).

Spiro[2H-1-benzopyran-2,1′-cyclopropane]-6-carboxylic acid,8-cyclopropyl-3,4-dihydro-4,4-dimethyl-,4-(tert-butoxycarbonylmethyl)phenyl ester (Compound 57, General Formula1)

A solution of spiro[2H-1-benzopyran-2,1′-cyclopropane]-6-carboxylicacid, 8-cyclopropyl-3,4-dihydro-4,4-dimethyl- (Intermediate 49, 0.06 g,0.22 mmol) in anhydrous dichloromethane (5 mL) was treated withtert-butyl-4-hydroxy phenyl acetate (Reagent E, 0.05 g, 0.22 mmol)followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(0.11 g, 0.22 mmol) and 4-dimethylaminopyridine (0.028 g, 0.22 mmol).The resulting solution was stirred at ambient temperature overnight. Thereaction mixture was subjected to flash column chromatography oversilica gel (230-400 mesh) using 7% ethyl acetate in hexane as the eluentto afford the title compound as a clear oil that solidified on standing(0.048 g, 48%).

¹H NMR (300 MHz, CDCl₃): δ 7.91 (d, 1H, J=2.1 Hz), 7.41 (d, 1H, J=1.8Hz), 7.24 (d, 2H, J=8.8 Hz), 7.05 (d, 2H, J=8.5 Hz), 3.46 (s, 2H),1.97-1.90 (m, 1H), 1.87 (s, 2H), 1.37 (s, 9H), 1.36 (s, 6H), 1.04-0.90(m, 2H), 0.87-0.75 (m, 2H), 0.65-0.56 (m, 4H).

Spiro[2H-1-benzopyran-2,1′-cyclopropane]-6-carboxylic acid,8-cyclopropyl-3,4-dihydro-4,4-dimethyl-, 4-(carboxymethyl)phenyl ester(Compound 58, General Formula 1)

A solution of spiro[2H-1-benzopyran-2,1′-cyclopropane]-6-carboxylicacid, 8-cyclopropyl-3,4-dihydro-4,4-dimethyl-,4-(tert-butoxycarbonylmethyl)phenyl ester (Compound 57, 0.048 g, 0.105mmol) was treated with 2 mL of trifluoroacetic acid and stirred atambient temperature for 2 h. The trifluoroacetic acid was distilled offunder reduced pressure and the residue was subjected to preparativereverse phase HPLC using 10% water in acetonitrile as the mobile phaseto afford the title compound as a white solid (0.029 g, 55%).

¹H NMR (300 MHz, CDCl₃): δ 7.99 (d, 1H, J=2.2 Hz), 7.48 (d, 1H, J=1.9Hz), 7.34 (d, 2H, J=8.5 Hz), 7.16 (d, 2H, J=8.5 Hz), 3.67 (s, 2H),2.07-1.97 (m, 1H), 1.95 (s, 2H), 1.44 (s, 6H), 1.09-1.04 (m, 2H),0.93-0.85 (m, 2H), 0.79-0.64 (m, 4H).

Spiro[2H-1-benzopyran-2,1′-cyclopropane]-6-carboxylic acid,8-cyclopropyl-3,4-dihydro-4,4-dimethyl-,3-(tert-butoxycarbonylmethyl)phenyl ester (Compound 59, General Formula1)

A solution of spiro[2H-1-benzopyran-2,1′-cyclopropane]-6-carboxylicacid, 8-cyclopropyl-3,4-dihydro-4,4-dimethyl- (Intermediate 49, 0.05 g,0.18 mmol) in anhydrous dichloromethane (5 mL) was treated withtert-butyl-3-hydroxy phenyl acetate (Reagent F, 0.04 g, 0.18 mmol)followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(0.029 g, 0.1 mmol) and 4-dimethylaminopyridine (0.022 g, 0.18 mmol).The resulting solution was stirred at ambient temperature overnight. Thereaction mixture was subjected to flash column chromatography oversilica gel (230-400 mesh) using 7% ethyl acetate in hexane as the eluentto afford the title compound as a clear oil that solidified on standing(0.020 g, 23%).

¹H NMR (300 MHz, CDCl₃): δ 7.98 (d, 1H, J=1.9 Hz), 7.48 (d, 1H, J=2.2Hz), 7.38 (t, 1H, J=7.7 Hz), 7.19-7.11 (m, 3H), 3.68 (s, 2H), 2.05-1.94(m, 1H), 1.95 (s, 2H), 1.44 (s, 15H), 1.09-1.04 (m, 2H), 0.96-0.82 (m,2H), 0.73-0.64 (m, 4H).

Spiro[2H-1-benzopyran-2,1′-cyclopropane]-6-carboxylic acid,8-cyclopropyl-3,4-dihydro-4,4-dimethyl-, 3-(carboxymethyl)phenyl ester(Compound 60, General Formula 1)

A solution of spiro[2H-1-benzopyran-2,1′-cyclopropane]-6-carboxylicacid, 8-cyclopropyl-3,4-dihydro-4,4-dimethyl-,3-(tert-butoxycarbonylmethyl)phenyl ester (Compound 59, 0.020 g, 0.04mmol) was treated with 2 mL of trifluoroacetic acid and stirred atambient temperature for 2 h. The trifluoroacetic acid was distilled offunder reduced pressure and the residue was subjected to preparativereverse phase HPLC using 10% water in acetonitrile as the mobile phaseto afford the title compound as a white solid (0.0125 g, 62%).

¹H NMR (300 MHz, CDCl₃): δ 7.99 (d, 1H, J=2.1 Hz), 7.49 (d, 1H, J=2.1Hz), 7.36 (t, 1H, J=7.8 Hz), 7.18-7.08 (m, 3H), 3.56 (s, 2H), 2.06-1.95(m, 1H), 1.95 (s, 2H), 1.45 (s, 6H), 1.09-1.05 (m, 2H), 0.96-0.84 (m,2H), 0.74-0.65 (m, 4H).

6-Bromo-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-1-carbaldehyde(Intermediate 50)

A solution of 6-bromo-4,4-dimethyl-1,2,3,4-tetrahydroquinoline,available in accordance with U.S. Pat. No. 5,089,509, the specificationof which is incorporated herein by reference (1.8 g, 7.5 mmol) in 10 mLof formic acid was refluxed for 3 h. The reaction mixture was thencooled to ambient temperature and poured into ice-cold saturated aqueoussodium bicarbonate solution and extracted with diethyl ether (×2). Thecombined organic phase was dried over anhydrous sodium sulfate, filteredand evaporated in vacuo to a residue which was subjected to flash columnchromatography over silica gel (230-400 mesh) using 15-25% ethyl acetatein hexane as the eluent to afford the title compound as a pale yellowsolid (1.8 g, 90%).

¹H NMR (300 MHz, CDCl₃): δ 8.71 (s, 1H), 7.45 (d, 1H, J=2.2 Hz), 7.28(dd, 1H, J=2.2, 8.5 Hz), 6.98 (d, 1H, J=8.5 Hz), 3.78 (t, 2H, J=6.3 Hz),1.74 (t, 2H, J=6.3 Hz), 1.28 (s, 6H).

6-Bromo-1-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydroquinoline(Intermediate 51)

A stirred, cooled (0° C.) solution of6-bromo-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-1-carbaldehyde(Intermediate 50, 21.8, 6.7 mmol) in anhydrous tetrahydrofuran (20 mL)under argon was treated with titanium tetra-iso-propoxide (2.15 mL, 7.39mmol) followed by 3M solution of ethyl magnesium bromide in diethylether (5.6 mL, 16.8 mmol) and the reaction mixture was then heated at50° C. overnight. It was then cooled in an ice-bath, quenched withsaturated aqueous ammonium chloride solution and extracted with diethylether (×2). The combined organic phase was dried over anhydrous sodiumsulfate, filtered over celite and evaporated in vacuo to residue whichwas subjected to flash column chromatography over silica gel (230-400mesh) using 5% ethyl acetate in hexane as the eluent to afford the titlecompound as an oil (1.2 g, 64%).

¹H NMR (300 MHz, CDCl₃): δ 7.24 (d, 1H, J=2.5 Hz), 7.12 (dd, 1H, J=2.2,8.8 Hz), 7.01 (d, 1H, J=8.8 Hz), 3.20 (t, 2H, J=6.0 Hz), 2.27-2.20 (m,1H), 1.68 (t, 2H, J=5.9 Hz), 1.24 (s, 3H), 1.23 (s, 3H), 0.83-0.77 (m,2H), 0.60-0.55 (m, 2H).

1-Cyclopropyl-6-trimethylsilanylethynyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline(Intermediate 52)

Following general procedure D and using6-bromo-1-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro quinoline(Intermediate 51, 0.8 g, 2.86 mmol), (trimethylsilyl)acetylene (5 mL, 35mmol), triethyl amine (10 mL), anhydrous tetrahydrofuran,copper(I)iodide (0.080 g, 0.42 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.240 g, 0.34 mmol), thetitle compound was obtained as an oil (0.67 g, 79%).

¹H NMR (300 MHz, CDCl₃): δ 7.33 (d, 1H, J=1.8 Hz), 7.22 (dd, 1H, J=2.1,8.5 Hz), 7.06 (d, 1H, J=8.5 Hz), 3.27 (t, 2H, J=5.9 Hz), 2.37-2.31 (m,1H), 1.70 (t, 2H, J=6.0 Hz), 1.28 (s, 6H), 0.89-0.82 (m, 2H), 0.66-0.60(m, 2H), 0.28 (s, 9H).

1-Cyclopropyl-6-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydroquinoline:(Intermediate 53)

Following general procedure E and using1-cyclopropyl-6-trimethylsilanylethynyl-4,4-dimethyl-1,2,3,4-tetrahydroquinoline(Intermediate 52, 0.40 g, 1.34 mmol), methanol and potassium carbonate(0.2 g, 1.47 mmol) followed by flash column chromatography over silicagel (230-400 mesh) using 2% ethyl acetate in hexane as the eluent, thetitle compound was obtained as an oil (0.17 g, 56%).

¹H NMR (300 MHz, CDCl₃): δ 7.38 (d, 1H, J=2.1 Hz), 7.27 (dd, 1H, J=2.1,8.5 Hz), 7.11 (d, 1H, J=8.5 Hz), 3.30 (t, 2H, J=6.0 Hz), 3.02 (s, 1H),2.40-2.34 (m, 1H), 1.74 (t, 2H, J=6.0 Hz), 1.30 (s, 6H), 0.93-0.85 (m,2H), 0.70-0.63 (m, 2H).

4-(1-Cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl-ethynyl)-benzoicacid ethyl ester (Compound 61, General Formula 7)

Following general procedure F and using1-cyclopropyl-6-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydro quinoline(Intermediate 53, 0.11 g, 0.43 mmol), ethyl-4-iodo-benzoate (Reagent A,0.11 g, 0.9 mmol), triethyl amine (3 mL), tetrahydrofuran(3 mL),copper(I)iodide(0.02 g, 0.1 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.060 g, 0.085 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using 5-10% ethyl acetate in hexane as the eluent, the title compoundwas obtained (0.05 g, 31%).

¹H NMR (300 MHz, CDCl₃): δ 7.99 (d, 2H, J=8.2 Hz), 7.54 (d, 2H, J=8.2Hz), 7.37 (d, 1H, J=2.1 Hz), 7.26 (dd, 1H, J=2.1, 8.5 Hz), 7.10 (d, 1H,J=8.8 Hz), 4.37 (q, 2H, J=7.1 Hz), 3.28 (t, 2H, J=6.0 Hz), 2.40-2.33 (m,1H), 1.71 (t, 2H, J=5.8 Hz), 1.40 (t, 3H, J=7.0 Hz), 1.27 (s, 6H),0.94-0.82 (m, 2H), 0.65-0.60 (m, 2H).

4-(1-Cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl-ethynyl)-benzoicacid (Compound 62, General Formula 7)

Following general procedure L and using4-(1-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-6-ylethynyl)-benzoicacid ethyl ester (Compound 61, 0.005 g, 0.13 mmol), 5 mL of ethanol and5M sodium hydroxide solution (2 mL) followed by recrystallization fromhot ethyl acetate, the title compound was obtained as a solid (0.030 g,64%).

¹H NMR (300 MHz, DMSO-d₆): δ 7.92 (d, 2H, J=8.2 Hz), 7.57 (d, 2H, J=8.2Hz), 7.33 (d, 1H, J=1.9 Hz), 7.23 (dd, 1H, J=1.9, 8.5 Hz), 7.06 (d, 1H,J=8.8 Hz), 3.25 (t, 2H, J=5.8 Hz), 2.41-2.34 (m, 1H), 1.64 (t, 2H, J=5.6Hz), 1.21 (s, 6H), 0.87-0.81 (m, 2H), 0.59-0.54 (m, 2H).

[4-(1-Cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl-ethynyl)phenyl]acetic acid methyl ester (Compound 63, General Formula 7)

Following general procedure F and using1-cyclopropyl-6-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydro quinoline(Intermediate 53, 0.05 g, 0.22 mmol), methyl-4-iodo-phenyl acetate(Reagent B, 0.055 g, 0.2 mmol), triethyl amine (5 mL), tetrahydrofuran,copper(I)iodide(0.025 g, 0.13 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.75 g, 0.11 mmol)followed preparative normal phase HPLC using 10% ethyl acetate in hexaneas the mobile phase, the title compound was obtained (0.089 g, 100%).

¹H NMR (300 MHz, CDCl₃): δ 7.47 (d, 2H, J=8.8 Hz), 7.45 (d, 1H, J=1.8Hz), 7.35-7.22 (m, 2H), 7.10 (d, 2H, J=8.8 Hz), 3.70 (s, 3H), 3.63 (s,2H), 3.27 (t, 2H, J=6.0 Hz), 2.37-2.31 (m, 1H), 1.71 (t, 2H, J=6.0 Hz),1.27 (s, 6H), 0.89-0.81 (m, 2H), 0.65-0.60 (m, 2H).

[4-(1-Cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl-ethynyl)-2-fluoro-phenyl]acetic acid ethyl ester (Compound 64, General Formula 7)

Following general procedure F and using1-cyclopropyl-6-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydro quinoline(Intermediate 53, 0.11 g, 0.49 mmol), ethyl-2-fluoro-4-iodo-phenylacetate (Reagent C, 0.11 g, 0.9 mmol), triethyl amine (3 mL),tetrahydrofuran(3 mL), copper(I)iodide(0.06 g, 0.32 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.25 g, 0.36 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using 10% ethyl acetate in hexane as the eluent, the title compound wasobtained (0.1 g, 51%).

¹H NMR (300 MHz, CDCl₃): δ 7.34 (d, 1H, J=2.1 Hz), 7.25-7.17 (m, 3H),7.09 (d, 2H, J=8.8 Hz), 4.17 (q, 2H, J=7.1 Hz), 3.65 (s, 2H), 3.27 (t,2H, J=6.0 Hz), 2.38-2.31 (m, 1H), 1.69 (t, 2H, J=6.0 Hz), 1.27 (s, 6H),1.25 (t, 3H, J=7.1 Hz), 0.88-0.81 (m, 2H), 0.65-0.59 (m, 2H).

N-(4-Bromophenyl)-N-methyl-3-methyl-2-butenamide (Intermediate 54)

3,3-Dimethylacryloyl chloride (3 mL, 27 mmol) was added to a solution of4-bromo-N-methyl-aniline (4.55 g, 25 mmol) in 150 mL of dichloromethanefollowed after 5 minutes by triethyl amine (5 mL, 33 mmol). After 2.5 hat ambient temperature, the reaction mixture was washed with water andthe organic phase was dried over anhydrous sodium sulfate and evaporatedin vacuo to afford the title product as a brown oil in quantitativeyield.

¹H-NMR (300 MHz, CDCl₃): d 1.71 (s, 3H), 2.11(s, 3H), 3.28(s, 3H),5.47(s, 1H), 7.05(d, J=8.5 Hz, 2H), 7.50(d, J=8.2 Hz, 2H).

6-Bromo-1,4,4-trimethyl-2-oxo-1,2,3,4-tetrahydroquinoline (Intermediate55)

N-(4-bromophenyl)-N-methyl-3-methyl-2-butenamide (Intermediate 54, 6.42g, 24 mmol) was heated to 130° C. and aluminum chloride (5 g, 37.4 mmol)was added in portions over 0.5 h. The reaction mixture was stirred for 1hour at the same temperature and then cooled to room temperature. Icewas added cautiously to the solid, followed by ˜200 mL of iced water.The reaction mixture was then extracted with ether (×2) anddichloromethane (×1) and the combined organic phase was dried overanhydrous magnesium sulfate and evaporated in vacuo to yield a brownsolid. The solid was treated with hexane-dichloromethane and filtered toafford 1.7 g of product. The mother liquor was evaporated and purifiedby flash column chromatography on silica gel (230-400 mesh) to afford2.9 g of the title compound as a solid (total 72%).

¹H-NMR (300 MHz, CDCl₃): δ1.29(s, 6H), 2.49(s, 2H), 3.36(s, 3H), 6.87(d,J=8.2 Hz, 1H), 7.36(dd, J=2.0, 8.5 Hz, 1H), 7.39(d, J=2.0 Hz, 1H).

6-Bromo-1,4,4-trimethylspiro[2H-1-1,2,3,4-tetrahydroquinoline-2,1′-cyclopropane](Intermediate 56)

A stirred, cooled (−78° C.) 3M solution of ethyl magnesium bromide inether (8.1 mL, 24.25 mmol) under argon was treated with anhydroustetrahydrofuran (20 mL) followed by a solution of titaniumtetra-iso-propoxide (3.15 mL, 10.2 mmol) in tetrahydrofuran (10 mL). Asolution of 6-bromo-1,4,4-trimethyl-2-oxo-1,2,3,4-tetrahydroquinoline(Intermediate 55, 2.6 g, 9.7 mmol) was cannulated into the reactionmixture and the solution was allowed to warm to room temperatureovernight. It was then cooled in an ice-bath, quenched with saturatedaqueous ammonium chloride solution, filtered over celite and the aqueousphase was extracted with diethyl ether (×2). The combined organic phasewas dried over anhydrous magnesium sulfate, filtered and evaporated invacuo to afford an orange oil. Flash column chromatography over silicagel (230-400 mesh) using 2-4% ethyl acetate in hexane as the eluentafforded the title compound as an oil which was ˜70% pure (1.7 g, 63%)and 0.5 g of recovered starting material.

¹H-NMR (300 MHz, CDCl₃): δ 0.58(t, J=6.0 Hz, 2H), 0.91(t, J=6.0 Hz, 2H),1.35 (s, 6H), 1.70(s, 2H), 2.68 (s, 3H), 6.59 (d, J=8.8 Hz, 1H),7.16(dd, J=2.3, 8.8 Hz, 1H), 7.33(d, J=2.3 Hz, 1H).

1,4,4-Trimethyl-6-(trimethylsilanyl)ethynylspiro[2H-1-1,2,3,4-tetrahydroquinoline-2,1′-cyclopropane](Intermediate 57)

Following general procedure D and using6-bromo-1,4,4-trimethylspiro[2H-1-1,2,3,4-tetrahydroquinoline-2,1′-cyclopropane](Intermediate 56, 0.56 g, 2 mmol), (trimethylsilyl)acetylene (1.13 mL, 8mmol), triethyl amine (4 mL), anhydrous tetrahydrofuran (5 mL),copper(I)iodide (0.08 g, 0.4 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.28 g, 0.4 mmol),followed by flash column chromatography over silica gel (230-400 mesh)using hexane-2% ethyl acetate in hexane as the eluent, the titlecompound was obtained as an oil (0.42 g, 70%).

¹H NMR (300 MHz, CDCl₃): δ 0.023(s, 9H), 0.33(t, J=6.1 Hz, 2H), 0.71(t,J=6.1 Hz, 2H), 1.10(s, 6H), 1.45(s, 2H), 2.41 (s, 3H), 6.31(d, J=8.5 Hz,1H), 6.96 (dd, J=2.1, 8.5 Hz, 1H), 7.10(d, J=2.1 Hz, 1H).

Benzoic acid,4-[(1,4,4-trimethylspiro[2H-1-1,2,3,4-tetrahydroquinoline-2,1′-cyclopropane]-6-yl)ethynyl]-ethylester (Compound 65, General Formula 1)

Following general procedure E and using a solution of1,4,4-trimethyl-6-(trimethylsilanyl)ethynylspiro[2H-1-1,2,3,4-tetrahydroquinoline-2,1′-cyclopropane](Intermediate 57, 0.416 g, 1.4 mmol), methanol (10 mL), ethyl acetate (2mL) and potassium carbonate (1.08 g, mmol) a silyl deprotectedacetylenic intermediate was obtained which was used directly for thenext step (0.25 g, 79%). Following general procedure F and using part ofthe acetylenic intermediate obtained as above (0.11 g, 0.5 mmol),ethyl-4-iodo benzoate (Reagent A, 0.112 g, 0.4 mmol), triethyl amine (1mL), tetrahydrofuran (2.5 mL), copper(I)iodide (0.050 g, 0.26 mmol) andtetrakis(triphenylphosphine)palladium(0)(0.096 g) followed by flashcolumn chromatography over silica gel (230-400 mesh) using 8% ethylacetate in hexane as the eluent and preparative HPLC on Partisil 10silica column using 10% ethyl acetate in hexane as the mobile phase, thetitle compound was obtained as a yellow oil (0.048 g, 26%).

¹H-NMR (300 MHz, CDCl₃): δ 0.60 (t, J=6.1 Hz, 2H), 0.99(t, J=6.1 Hz,2H), 1.37(s, 6H), 1.42(t, J=7.0 Hz, 3H), 1.73(s, 2H), 2.68(s, 3H), 4.40(q, J=7.0 Hz, 2H), 6.61(d, J=8.8 Hz, 1H), 7.28 (dd, J=2.1, 8.5 Hz, 1H),7.42 (d, J=2.1 Hz, 1H), 7.57(d, J=8.2 Hz, 2H), 8.01(d, J=8.2 Hz, 2H).

Benzoic acid,4-[(1,4,4-trimethylspiro[2H-1-1,2,3,4-tetrahydroquinoline-2,1′-cyclopropane]-6-yl)ethynyl]-(Compound 66, General Formula 1)

Following general procedure I and using benzoic acid,4-[(1,4,4-trimethylspiro[2H-1-1,2,3,4-tetrahydroqunoline-2,1′-cyclopropane]-6-yl)ethynyl]-ethylester (Compound 65, 0.03 g, 0.08 mmol), ethanol (2 mL), tetrahydrofuran(2 mL) and 1M aqueous sodium hydroxide solution (1 mL), the titlecompound was obtained as a yellow solid (0.020 g, 67%).

¹H-NMR (300 MHz, CD₃COCD₃): δ 0.60 (t, J=5.8 Hz, 2H), 1.03(t, J=5.8 Hz,2H), 1.34(s, 6H), 1.74(s, 2H), 2.69(s, 3H), 6.60(d, J=8.5 Hz, 1H), 7.23(dd, J=2.0, 8.4 Hz, 1H), 7.39 (d, J=2.0 Hz, 1H), 7.58(d, J=8.2 Hz, 2H),8.01(d, J=8.2 Hz, 2H).

Esterification Methods:

Method A:

The carboxylic acid was combined with a solution of the desired alcoholand concentrated sulfuric acid (20 to 1 v/v) and the resulting mixtureor solution (0.75 to 1.0 M) heated to reflux overnight. The solution wascooled to room temperature, diluted with Et₂O, and washed with H₂O,saturated aqueous NaHCO₃, and saturated aqueous NaCl before being driedover MgSO₄. Concentration of the dry solution under reduced pressureafforded the desired carboxylic ester of sufficient purity to be useddirectly in the next reaction.

Method B:

To a solution (0.67 to 1.0M) of the carboxylic acid in acetone was added1.1 equivalents of the desired alkyl halide and 1.0 equivalents of solidpotassium carbonate. The resulting mixture was heated to reflux for 2 hand then allowed to stir at room temperature overnight. The mixture wasfiltered and the filtrate concentrated under reduced pressure. Theproduct was isolated from the residue by column chromatography usingsilica gel as the solid phase.

Method C:

A solution (1M) of the carboxylic acid in thionyl chloride was heated atreflux until analysis of a reaction aliquot by IR spectroscopy showedthe absence of the aryl carboxylic acid carbonyl band (1705-1680 cm⁻¹).The solution was cooled to room temperature and concentrated underreduced pressure to give the crude acyl chloride.

The acyl chloride was dissolved in CH₂Cl₂ and the resulting solution(0.5 to 0.75M) treated with 1.1 equivalents the desired alcohol and 2.0equivalents of pyridine. After stirring overnight at room temperaturethe solution was diluted with Et₂O and washed with H₂O, 10% aqueous HCl,saturated aqueous NaHCO₃, and saturated aqueous NaCl before being driedover Na₂SO₄. Concentration of the dry solution under reduced pressurefollowed by column chromatography afforded the desired ester.

General Procedure 1 (preparation of Enol ethers):

A solution (0.35 M) of the aryl ester in anhydrous THF was cooled to 0°C. and treated with 1.0 equivalents of Tebbe's Reagent([μ-chloro-μ-methylene[bis(cyclopentadienyl)titanium]-dimethylaluminium]0.5 M in toluene). After 30 minutes the solution was warmed to roomtemperature and stirred for 30 minutes before being carefully added to a0.1 N NaOH solution at 0° C. This mixture was treated with hexanes andthe solids removed by filtration through a pad of Celite. The solidswere washed with hexanes and the filtrate passed through a second pad ofCelite to remove any newly formed solids. The organic layer was dried(Na₂SO₄) and concentrated under reduced pressure. The desired enol etherwas isolated from the residue by column chromatography using 1-2% ofEt₃N added to the eluant. (note: prolonged exposure of the product tothe column can result in hydrolysis and formation of the correspondingmethyl ketone.)

General Procedure 2 (cyclopropanation of the enol ethers):

To a solution (0.3 M) of the enol ether in anhydrous Et₂O was added 2.0equivalent of Et₂Zn (as a solution in hexanes) and 2.0 equivalents ofCH₂I₂. The resulting solution was heated to reflux until analysis of areaction aliquot (by TLC or ¹H NMR) indicated that all of the startingenol ether had been consumed. (note: Additional equal amounts of Et₂Znand CH₂I₂ can be added to drive the reaction to completion.) Uponcooling to room temperature the reaction was carefully quenched by theaddition of saturated aqueous NH₄Cl. The resulting mixture is extractedwith Et₂O and the combined organic layers washed with H₂O and saturatedaqueous NaCl before being dried over Na₂SO₄ and concentrated underreduced pressure. The product is isolated from the residue by columnchromatography.

1-Bromo-4-(1-methoxyvinyl)-benzene: (Intermediate 58)

Using General Procedure 1; methyl 4-bromo-benzoate (600.0 mg, 2.78mmols), and 5.6 mL of Tebbe's Reagent (794.0 mg, 2.78 mmols) afforded420.0 mg (70%) of the title compound as a colorless oil after columnchromatography (100% hexanes).

¹H NMR (CDCl₃) δ: 7.48-7.45 (4H, m), 4.64 (1H, d, J=2.9 Hz), 4.23 (1H,d, J=2.9 Hz), 3.73 (3H, s).

1-Bromo-4-(1-methoxycyclopropyl)-benzene (Intermediate 59)

Using General Procedure 2; 1-bromo-4-(1-methoxyvinyl)-benzene(Intermediate 58, 410.0 mg, 1.92 mmols), Et₂Zn (711.3 mg, 5.76 mmols),and CH₂I₂ (1.54 g, 5.76 mmols) in 4.0 mL Et₂O afforded 300.0 mg (69%) ofthe title compound as a colorless oil after chromatography (0-3%EtOAc—hexanes).

¹H NMR (CDCl₃) δ: 7.46 (2H, d, J=8.5 Hz), 7.18 (2H, d, J=8.5 Hz), 3.21(3H, s), 1.19 (2H, m), 0.94 (2H, m).

[4-(1-Methoxycyclopropyl)-phenylethynyl]-trimethylsilane (Intermediate60)

Using General Procedure D; 1-bromo-4-(1-methoxycyclopropyl)-benzene(Intermediate 59, 300.0 mg, 1.32 mmol) in triethylamine (4 mL) andanhydrous tetrahydrofuran (4 mL) was treated with copper(I)iodide (93.0mg, 0.13 mmol) and then sparged with argon for 5 minutes. Trimethylsilylacetylene (1.39 g, 14.2 mmols) was then added followed bydichlorobis(triphenylphosphine)palladium(II) (93.0 mg, 0.13 mmol). Theresulting reaction mixture was heated to 70° C. for 60 h. The titlecompound (286.0 mg, 90%) was isolated by chromatography (0-3%EtOAc—hexanes).

¹H NMR (CDCl₃) δ: 7.35 (2H, d, J=7.2 Hz), 7.14 (2H, d, J=7.2 Hz), 3.14(3H, s), 1.14 (2H, m), 0.88 (2H, m), 0.17 (9H, s).

1-Ethynyl-4-(1-methoxycyclopropyl)-benzene (Intermediate 61)

Using General Procedure E;[4-(1-methoxycyclopropyl)-phenylethynyl]-trimethylsilane (Intermediate60, 285.0 mg, 1.18 mmols) in methanol (10 mL) was treated with potassiumcarbonate (100.0 mg, 0.72 mmol) and stirred overnight at ambienttemperature. The crude alkyne (220 mg, 100%) was used directly in thenext reaction.

¹H NMR (CDCl₃) δ: 7.46 (2H, d, J=8.2 Hz), 7.24 (2H, d, J=8.2 Hz), 3.23(3H, s), 3.06 (1H, s), 1.22 (2H, m), 0.98 (2H, m).

Ethyl 4-[4-(1-methoxycyclopropyl)-phenylethynyl]-benzoate (Compound 67,General Formula 2)

Using General Procedure F; 1-ethynyl-4-(1-methoxycyclopropyl)-benzene(Intermediate 61, 100.0 mg, 0.47 mmol) and ethyl-4-iodo benzoate(Reagent A, 141.0 mg, 0.51 mmol) in triethyl amine (6 mL) was treatedwith copper(I)iodide (30.0 mg, 0.16 mmol) and sparged with argon for 5minutes. Dichlorobis(triphenylphosphine)palladium(II) (109 mg, 0.16mmol) was added and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-5% EtOAc—hexanes) afforded 135.0mg (90%) of the title compound as an orange solid.

¹H NMR (CDCl₃) δ: 8.02 (2H, d, J=8.2 Hz), 7.58 (2H, d, J=8.8 Hz), 7.52(2H, d, J=8.2 Hz), 7.28 (2H, d, J=8.8 Hz), 4.39 (2H, q, J=7.1 Hz), 3.25(3H, s), 1.40 (3H, t, J=7.1 Hz), 1.23 (2H, m), 1.00 (2H, m).

Methyl{4-[4-(1-methoxycyclopropyl)-phenylethynyl]-phenyl}-acetate(Compound 68, General Formula 2)

Using General Procedure F; 1-ethynyl-4-(1-methoxycyclopropyl)-benzene(Intermediate 61, 120.0 mg, 0.56 mmol) and methyl-(4-iodophenyl)-acetate(Reagent B, 154.0 mg, 0.56 mmol) in triethyl amine (6 mL) was treatedwith copper(I)iodide (35.0 mg, 0.19 mmol) and sparged with argon for 5minutes. Dichlorobis(triphenylphosphine)palladium(II) (130 mg, 0.19mmol) was added and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-8% EtOAc—hexanes) afforded 140.0mg (78%) of the title compound as an orange solid.

¹H NMR (CDCl₃) δ: 7.50 (4H, d, J=8.1 Hz), 7.28 (4H, d, J=8.1 Hz), 3.76(3H, s), 3.64 (2H, s), 3.25 (3H, s), 1.22 (2H, m), 0.99 (2H, m).

4-[4-(1-Methoxycyclopropyl)-phenylethynyl]-benzoic acid (Compound 69,General Formula 2)

Using General Procedure I; a solution of ethyl4-[4-(1-methoxycyclopropyl)-phenylethynyl]-benzoate (Compound 67, 110.0mg, 0.34 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treatedwith NaOH (160.0 mg, 4.0 mmols, 2.0 mL of a 2N aqueous solution) andstirred overnight at room temperature. Work-up afforded 85.0 mg (86%) ofthe title compound as an orange solid.

¹H NMR (CDCl₃) δ: 8.05 (2H), 7.66 (2H), 7.56 (2H, d, J=8.5 Hz), 7.35(2H, d, J=8.6 Hz), 3.22 (3H, s), 1.21 (2H, m), 1.01 (2H, m).

{4-[4-(1-Methoxycyclopropyl)-phenylethynyl]-phenyl}-acetic acid(Compound 70, General Formula 2)

Using General Procedure I; a solution ofmethyl{4-[4-(1-methoxycyclopropyl)-phenylethynyl]-phenyl}-acetate(Compound 68, 100.0 mg, 0.31 mmol) in ethanol (3 mL) and tetrahydrofuran(3 mL) was treated with NaOH (160.0 mg, 4.0 mmols, 2.0 mL of a 2Naqueous solution) and stirred overnight at room temperature. Work-upafforded 80.0 mg (84%) of the title compound as an orange solid.

¹H NMR (CDCl₃) δ: 7.49 (4H), 7.27 (4H), 3.66 (2H, s), 3.25 (3H, s), 1.22(2H, m), 0.99 (2H, m).

Isopropyl 4-bromobenzoate (Intermediate 62)

Using General Esterification Procedure A; 4-bromobenzoic acid (1.50 g,7.46 mmols) was combined with isopropyl alcohol to give 1.76 g (97%) ofthe title compound as a colorless oil.

¹H NMR (CDCl₃) δ: 7.90 (2H, d, J=8.5 Hz), 7.57 (2H, d, J=8.5 Hz), 5.24(1H, septet, J=6.2 Hz), 1.37 (6H, d, J=6.2 Hz).

1-Bromo-4-(1-isopropoxyvinyl)-benzene (Intermediate 63)

Using General Procedure 1; isopropyl 4-bromobenzoate (Intermediate 62,780.0 mg, 3.20 mmols) and 6.4 mL of Tebbe's Reagent (910.7 mg, 3.20mmols) afforded 328.0 mg (43%) of the title compound as a colorless oilafter column chromatography (100% hexanes).

¹H NMR (CDCl₃) δ: 7.46 (4H, m), 4.66 (1H, d, J=2.6 Hz), 4.40 (1H,septet, J=6.2 Hz), 4.21 (1H, d, J=2.6 Hz), 1.34 (6H, d, J=6.2 Hz).

1-Bromo-4-(1-isopropoxycyclopropyl)-benzene (Intermediate 64)

Using General Procedure 2; 1-bromo-4-(1-isopropoxyvinyl)-benzene(Intermediate 63, 328.0 mg, 1.36 mmols), Et₂Zn (335.9 mg, 2.72 mmols),and CH₂I₂ (728.0 mg, 2.72 mmols) in 4.0 mL Et₂O afforded 240.0 mg (70%)of the title compound as a colorless oil after chromatography (3%EtOAc—hexanes).

¹H NMR (CDCl₃) δ: 7.43 (2H, d, J=8.5 Hz), 7.27 (2H, d, J=8.5 Hz), 3.70(1H, septet, J=6.2 Hz), 1.18 (2H, m), 1.06 (6H, d, J=6.2 Hz), 0.91 (2H,m).

[4-(1-Isopropoxycyclopropyl)-phenylethynyl]-trimethylsilane(Intermediate 65)

Using General Procedure D; 1-bromo-4-(1-isopropoxycyclopropyl)-benzene(Intermediate 64, 240.0 mg, 0.94 mmol) in triethylamine (8 mL) treatedwith copper(I)iodide (18.0 mg, 0.094 mmol) and then sparged with argonfor 5 minutes. Trimethylsilyl acetylene (0.70 g, 7.1 mmols) was thenadded followed by dichlorobis-(triphenylphosphine)palladium(II) (66.0mg, 0.094 mmol). The resulting reaction mixture was heated to 70° C. for5 days. The title compound (250.0 mg, 98%) was isolated bychromatography (0-3% EtOAc—hexanes) as an orange oil.

¹H NMR (CDCl₃) δ: 7.41 (2H, d, J=7.9 Hz), 7.31 (2H, d, J=7.9 Hz), 3.70(1H, septet, J=6.2 Hz), 1.18 (2H, m), 1.05 (6H, d, J=6.2 Hz), 0.93 (2H,m), 0.94 (9H, s).

1-Ethynyl-4-(1-isopropoxycyclopropyl)-benzene (Intermediate 66)

Using General Procedure E;[4-(1-isopropoxycyclopropyl)-phenylethynyl]-trimethylsilane(Intermediate 65, 260.0 mg, 0.96 mmol) in methanol (10 mL) was treatedwith potassium carbonate (100.0 mg, 0.72 mmol) and stirred overnight atambient temperature. The crude alkyne (220 mg, 100%) was used directlyin the next reaction.

¹H NMR (CDCl₃) δ: 7.45 (2H, d, J=8.8 Hz), 7.35 (2H, d, J=8.8 Hz), 3.72(1H, septet, J=6.2 Hz), 3.06 (1H, s), 1.20 (2H, m), 1.07 (6H, d, J=6.2Hz), 0.95 (2H, m).

Ethyl 4-[4-(1-isopropoxycyclopropyl)-phenylethynyl]-benzoate (Compound71, General Formula 2)

Using General Procedure F; 1-ethynyl-4-(1-isopropoxycyclopropyl)-benzene(Intermediate 66, 114.0 mg, 0.57 mmol) and ethyl-4-iodo benzoate(Reagent A, 731.0 mg, 0.63 mmol) in triethylamine (8 mL) was treatedwith copper(I)iodide (36.0 mg, 0.19 mmol) and sparged with argon for 5minutes. Dichlorobis(triphenylphosphine)palladium(II) (133 mg, 0.19mmol) was added and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-4% EtOAc—hexanes) afforded 151.0mg (76%) of the title compound as an orange solid.

¹H NMR (CDCl₃) δ: 8.02 (2H, d, J=7.6 Hz), 7.58 (2H, d, J=7.6 Hz), 7.50(2H, d, J=7.8 Hz), 7.39 (2H, d, J=7.8 Hz), 4.39 (2H, q, J=7.1 Hz), 3.74(1H, septet, J=6.2 Hz), 1.40 (3H, t, J=7.1 Hz), 1.22 (2H, m), 1.08 (6H,d, J=6.2 Hz), 0.97 (2H, m).

Methyl{4-[4-(1-isopropoxycyclopropyl)-phenylethynyl]-phenyl}-acetate(Compound 72, General Formula 2)

Using General Procedure F; 1-ethynyl-4-(1-isopropoxycyclopropyl)-benzene(Intermediate 66, 95.0 mg, 0.45 mmol) and methyl-(4-iodophenyl)-acetate(Reagent B, 131.0 mg, 0.45 mmol) in triethylamine (6 mL) was treatedwith copper(I)iodide (30.0 mg, 0.16 mmol) and sparged with argon for 5minutes. Dichlorobis(triphenylphosphine)palladium(II) (111 mg, 0.16mmol) was added and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-8% EtOAc—hexanes) afforded 110.0mg (70%) of the title compound as an orange oil.

¹H NMR (CDCl₃) δ: 7.20 (4H), 7.08 (2H, d, J=7.0 Hz), 6.97 (2H, d, J=7.9Hz), 3.45 (1H, septet, J=6.2 Hz), 3.41 (3H, s), 3.35 (2H, s), 0.91 (2H,m), 0.79 (6H, d, J=6.2 Hz), 0.68 (2H, m).

4-[4-(1-Isopropoxycyclopropyl)-phenylethynyl]-benzoic acid (Compound 73,General Formula 2)

Using General Procedure I; a solution of ethyl4-[4-(1-isopropoxycyclopropyl)-phenylethynyl]-benzoate (Compound 71,110.0 mg, 0.32 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) wastreated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution)and stirred overnight at room temperature. Work-up afforded 89.0 mg(88%) of the title compound as a yellow solid.

¹H NMR (CDCl₃) δ: 8.06 (2H, d, J=8.2 Hz), 7.66 (2H, d, J=8.2 Hz), 7.55(2H, d, J=8.2 Hz), 7.46 (2H, d, J=8.2 Hz), 3.73 (1H, septet, J=6.2 Hz),1.18 (2H, m), 1.04 (6H, d, J=6.2 Hz), 0.99 (2H, m).

{4-[4-(1-Isopropoxycyclopropyl)-phenylethynyl]-phenyl}-acetic acid(Compound 74, General Formula 2)

Using General Procedure I; a solution ofmethyl{4-[4-(1-isopropoxycyclopropyl)-phenylethynyl]-phenyl}-acetate(Compound 72, 80.0 mg, 0.23 mmol) in ethanol (3 mL) and tetrahydrofuran(3 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueoussolution) and stirred overnight at room temperature. Work-up afforded48.0 mg (56%) of the title compound as a solid.

¹H NMR (CDCl₃) δ: 7.20 (2H, d, J=8.2 Hz), 7.19 (2H, d, J=8.8 Hz), 7.09(2H, d, J=8.8 Hz), 6.98 (2H, d, J=8.2 Hz), 3.46 (1H, septet, J=6.2 Hz),3.37 (2H, s), 0.92 (2H, m), 0.79 (6H, d, J=6.2 Hz), 0.67 (2H, m).

Benzyl 4-bromobenzoate (Intermediate 67)

Using General Esterification Method B; 4-bromobenzoic acid (2.01 g, 10.0mmols), benzyl bromide (1.89 g, 11.1 mmols), and K₂CO₃ (1.40 g, 10.0mmols) afforded 2.33 g (80%) of the title compound as a colorless solidafter column chromatography (3-10% EtOAc—hexanes).

¹H NMR (CDCl₃) δ: 7.89 (2H, d, J=8.5 Hz), 7.52 (2H, d, J=8.5 Hz),7.43-7.31 (5H), 5.33 (2H, s).

1-Bromo-4-(1-benzyloxyvinyl)-benzene (Intermediate 68)

Using General Procedure 1; benzyl 4-bromobenzoate (Intermediate 67,920.0 mg, 3.16 mmols) and 6.3 mL of Tebbe's Reagent (897.0 mg, 3.16mmols) afforded 640.0 mg (70%) of the title compound after columnchromatography (100% hexanes).

¹H NMR (CDCl₃) δ: 7.55-7.35 (9H), 4.95 (2H, s), 4.73 (1H, d, J=2.9 Hz),4.34 (1H, d, J=2.9 Hz).

1-Bromo-4-(1-benzyloxycyclopropyl)-benzene (Intermediate 69)

Using General Procedure 2; 1-bromo-4-(1-benzyloxyvinyl)-benzene(Intermediate 68, 280.0 mg, 0.97 mmol), Et₂Zn (247.0 mg, 2.0 mmols), andCH₂I₂ (536.0 mg, 2.0 mmols) in 2.0 mL Et₂O afforded 159.0 mg (53%) ofthe title compound as a colorless solid after chromatography (2-5%EtOAc—hexanes).

¹H NMR (CDCl₃) δ: 7.49-7.24 (9H), 4.41 (2H, s), 1.29 (2H, m), 1.00 (2H,m).

[4-(1-Benzyloxycyclopropyl)-phenylethynyl]-trimethylsilane (Intermediate70)

Using General Procedure D; 1-bromo-4-(1-benzyloxycyclopropyl)-benzene(Intermediate 69, 160.0 mg, 0.53 mmol) in triethylamine (5 mL) wastreated with copper(I)iodide (10.0 mg, 0.05 mmol) and then sparged withargon for 5 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) wasthen added followed by dichlorobis-(triphenylphosphine)palladium(II)(37.0 mg, 0.05 mmol). The resulting reaction mixture was heated to 70°C. for 5d. The title compound (150.0 mg, 83%) was isolated bychromatography (0-3% EtOAc—hexanes) as a pale-yellow oil.

¹H NMR (CDCl₃) δ: 7.21 (3H, m), 7.09-7.01 (6H, m), 4.18 (2H, s), 1.07(2H, m), 0.79 (2H, m), 0.02 (9H, s).

1-Ethynyl-4-(1-benzyloxycyclopropyl)-benzene (Intermediate 71)

Using General Procedure E;[4-(1-benzyloxycyclopropyl)-phenylethynyl]-trimethylsilane (Intermediate70, 150.0 mg, 0.47 mmols) in methanol (6 mL) was treated with potassiumcarbonate (100.0 mg, 0.72 mmol) and stirred overnight at ambienttemperature. The crude alkyne (115 mg, 100%) was used directly in thenext reaction.

¹H NMR (CDCl₃) δ: 7.67-7.50 (2H, d, J=8.2 Hz), 7.34-7.26 (7H, m), 4.43(2H, s), 3.07 (1H, s), 1.32 (2H, m), 1.04 (2H, m).

Ethyl 4-[4-(1-benzyloxycyclopropyl)-phenylethynyl]-benzoate (Compound75, General Formula 2)

Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)-benzene(Intermediate 71, 60.0 mg, 0.24 mmol) and ethyl-4-iodo benzoate (ReagentA, 72.0 mg, 0.26 mmol) in triethylamine (4 mL) was treated withcopper(I)iodide (17.0 mg, 0.09 mmol) and sparged with argon for 5minutes. Dichlorobis(triphenylphosphine)palladium(II) (61 mg, 0.09 mmol)was added and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-4% EtOAc—hexanes) afforded 85.0 mg(91%) of the title compound as an orange oil.

¹H NMR (CDCl₃) δ: 8.03 (2H, d, J=8.2 Hz), 7.62-7.54 (4H, m), 7.39-7.26(7H, m), 4.47 (2H, s), 4.40 (2H, q, J=7.1 Hz), 1.42 (3H, t, J=7.1 Hz),1.36 (2H, m), 1.07 (2H, m).

Methyl{4-[4-(1-benzyloxycyclopropyl)-phenylethynyl]-phenyl}-acetate(Compound 76, General Formula 2)

Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)-benzene(Intermediate 71, 60.0 mg, 0.20 mmol) and methyl-(4-iodophenyl)-acetate(Reagent B, 66.0 mg, 0.24 mmol) in triethylamine (5 mL) was treated withcopper(I)iodide (15.0 mg, 0.08 mmol) and sparged with argon for 5minutes. Dichlorobis(triphenylphosphine)palladium(II) (56 mg, 0.08 mmol)was added and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-7% EtOAc—hexanes) afforded 64.0 mg(81%) of the title compound as a yellow oil.

¹H NMR (CDCl₃) δ: 7.52-7.47 (4H, m), 7.37-7.25 (9H, m), 4.44 (2H, s),3.70 (3H, s), 3.64 (2H, s), 1.32 (2H, m), 1.06 (2H, m).

4-[4-(1-Benzyloxycyclopropyl)-phenylethynyl]-benzoic acid (Compound 77,General Formula 2)

Using General Procedure I; a solution of ethyl4-[4-(1-benzyloxycyclopropyl)-phenylethynyl]-benzoate (Compound 75, 78.0mg, 0.20 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treatedwith NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) andstirred overnight at room temperature. Work-up afforded 65.0 mg (89%) ofthe title compound as a solid.

¹H NMR (CDCl₃) δ: 7.97 (2H, d, J=8.5 Hz), 7.67 (2H, d, J=8.7 Hz), 7.58(2H, d, J=8.5 Hz), 7.41-7.28 (7H, m), 4.44 (2H, s), 1.33 (2H, m), 1.12(2H, m).

{4-[4-(1-Benzyloxycyclopropyl)-phenylethynyl]-phenyl}-acetic acid(Compound 78, General Formula 2)

Using General Procedure I; a solution ofmethyl{4-[4-(1-benzyloxycyclopropyl)-phenylethynyl]-phenyl}-acetate(Compound 76, 45.0 mg, 0.11 mmol) in ethanol (3 mL) and tetrahydrofuran(3 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueoussolution) and stirred overnight at room temperature. Work-up afforded35.0 mg (81%) of the title compound as a pale-yellow solid.

¹H NMR (CDCl₃) δ: 7.49 (4H, m), 7.37-7.25 (9H, m), 4.44 (2H, s), 3.66(2H, s), 1.32 (2H, m), 1.05 (2H, m).

Benzyl 4-bromo-2-methylbenzoate (Intermediate 72)

Using General Esterification Method C; 2-methyl-4-bromo-benzoic acid(2.15 g, 10.0 mmols) was refluxed for 3 h with 10 mL SOCl₂. Theresulting solution concentrated under reduced pressure and the crudeacyl chloride was combined with benzyl alcohol (1.08 g, 10.0 mmols) andpyridine (1.6 mL, 20.0 mmols) to give the title compound (2.4 g, 80%)after work-up and column chromatography (2-5% EtOAc—hexanes) as acolorless oil.

¹H NMR (CDCl₃) δ: 7.81 (1H, d, J=8.5 Hz), 7.41-7.33 (7H, m), 5.32 (2H,s), 2.57 (3H, s).

4-Bromo-1-(1-benzyloxyvinyl)-2-methylbenzene (Intermediate 73)

Using General Procedure 1; benzyl 4-bromo-2-methylbenzoate (Intermediate72, 840.0 mg, 2.77 mmols) and 5.4 mL of Tebbe's Reagent (788.0 mg, 2.77mmols) afforded 640.0 mg (76%) of the title compound after columnchromatography (100% hexanes).

¹H NMR (CDCl₃) δ: 7.38-7.19 (8H, m), 4.88 (2H, s), 4.45 (1H, d, J=2.6Hz), 4.25 (2H, d, J 2.6 Hz), 2.35 (3H, s).

4-Bromo-1-(1-benzyloxycyclopropyl)-2-methyl-benzene (Intermediate 74)

Using General Procedure 2; 4-bromo-1-(1-benzyloxyvinyl)-2-methyl-benzene(Intermediate 73, 400.0 mg, 1.32 mmols), Et₂Zn (325.0 mg, 2.63 mmols),and CH₂I₂ (704.0 mg, 2.63 mmols) in 4 mL Et₂O afforded 380.0 mg (90%) ofthe title compound as a colorless oil after chromatography (2-5%EtOAc—hexanes).

¹H NMR (CDCl₃) δ: 7.42-7.20 (8H, m), 4.31 (2H, s), 2.58 (3H, s), 1.25(2H, m), 0.94 (2H, m).

[4-(1-Benzyloxycyclopropyl)-3-methyl-phenylethynyl]-trimethylsilane(Intermediate 75)

Using General Procedure D;4-bromo-1-(1-benzyloxycyclopropyl)-2-methyl-benzene (Intermediate 74,320.0 mg, 1.00 mmol) in triethylamine (8 mL) was treated withcopper(I)iodide (19.0 mg, 0.1 mmol) and then sparged with argon for 5minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then addedfollowed by dichlorobis-(triphenylphosphine)palladium(II) (70.0 mg, 0.05mmol). The resulting reaction mixture was heated to 70° C. for 5d. Thetitle compound (300.0 mg, 89%) was isolated by chromatography (0-2%EtOAc—hexanes).

¹H NMR (CDCl₃) δ: 7.34-7.13 (8H, m), 4.24 (2H, s), 2.52 (3H, s), 1.20(2H, m), 0.88 (2H, m), 0.25 (9H, s).

4-Ethynyl-1-(1-benzyloxycyclopropyl)-2-methyl-benzene (Intermediate 76)

Using General Procedure E;[4-(1-benzyloxycyclopropyl)-3-methyl-phenylethynyl]-trimethylsilane(Intermediate 75, 300.0 mg, 0.95 mmols) in methanol (6 mL) was treatedwith potassium carbonate (120.0 mg, 0.87 mmol) and stirred overnight atambient temperature. The crude alkyne (185 mg, 79%) was used directly inthe next reaction.

¹H NMR (CDCl₃) δ: 7.37-7.16 (8H, m), 4.27 (2H, s), 3.07 (1H, s), 2.55(3H, s), 1.21 (2H, m), 0.92 (2H, m).

Ethyl 4-[4-(1-benzyloxycyclopropyl)-3-methyl-phenylethynyl]-benzoate(Compound 79, General Formula 2)

Using General Procedure F;1-ethynyl-4-(1-benzyloxycyclopropyl)-3-methyl-benzene (Intermediate 76,90.0 mg, 0.34 mmol) and ethyl-4-iodo benzoate (Reagent A, 95.0 mg, 0.34mmol) in triethylamine (6 mL) was treated with copper(I)iodide (23.0 mg,0.12 mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)palladium(II) (80 mg, 0.11 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-4% EtOAc—hexanes) afforded 68.0 mg(54%) of the title compound.

¹H NMR (CDCl₃) δ: 8.03 (2H, d, J=8.2 Hz), 7.58 (2H, d, J=8.2 Hz),7.33-7.16 (8H, m), 4.39 (2H, q, J=7.1 Hz), 4.29 (2H, s), 2.57 (3H, s),1.40 (3H, t, J=7.1 Hz), 1.22 (2H, m), 0.93 (2H, m).

Methyl{4-[4-(1-benzyloxycyclopropyl)-3-methyl-phenylethynyl]-phenyl}-acetate(Compound 80, General Formula 2)

Using General Procedure F;1-ethynyl-4-(1-benzyloxycyclopropyl)-3-methyl-benzene (Intermediate 76,90.0 mg, 0.34 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 95.0mg, 0.34 mmol) in triethylamine (5 mL) was treated with copper(I)iodide(22.0 mg, 0.11 mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)palladium(II) (80 mg, 0.11 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-4% EtOAc—hexanes) afforded 90.0 mg(71%) of the title compound as a pale-yellow oil.

¹H NMR (CDCl₃) δ: 7.49 (2H, d, J=8.2 Hz), 7.32-7.16 (10H, m), 4.28 (2H,s), 3.70 (3H, s), 3.64 (2H, s), 2.56 (3H, s), 1.22 (2H, m), 0.92 (2H,m).

4-[4-(1-Benzyloxycyclopropyl)-3-methyl-phenylethynyl]-benzoic acid(Compound 81, General Formula 2)

Using General Procedure I; a solution of ethyl4-[4-(1-benzyloxycyclopropyl)-3-methyl-phenylethynyl]-benzoate (Compound79, 68.0 mg, 0.17 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) wastreated with NaOH (360.0 mg, 9.0 mmols, 3.0 mL of a 3N aqueous solution)and stirred overnight at room temperature. Work-up afforded 48.0 mg(76%) of the title compound as a solid.

¹H NMR (CDCl₃) δ: 8.10 (2H, d, J=8.1 Hz), 7.63 (2H, d, J=8.1 Hz),7.44-7.16 (8H, m), 4.29 (2H, m), 2.58 (3H, s), 1.24 (2H, m), 0.94 (2H,m).

{4-[4-(1-Benzyloxycyclopropyl)-3-methyl-phenylethynyl]-phenyl}-aceticacid (Compound 82, General Formula 2)

Using General Procedure I; a solution ofmethyl{4-[4-(1-benzyloxycyclopropyl)-3-methyl-phenylethynyl]-phenyl}-acetate(Compound 80, 75.0 mg, 0.18 mmol) in ethanol (3 mL) and tetrahydrofuran(3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1Naqueous solution) and stirred overnight at room temperature. Work-upafforded 30.0 mg (40%) of the title compound.

¹H NMR (CDCl₃) δ: 7.51 (2H, d, J=8.2 Hz), 7.42 (1H, s), 7.33-7.17 (9H,m), 4.36 (2H, s), 3.67 (2H, s), 2.57 (3H, s), 1.23 (2H, m), 0.94 (2H,m).

Isopropyl 3-methyl-4-bromobenzoate (Intermediate 77)

Using General Esterification Procedure A; 4-bromo-2-methylbenzoic acid(1.6 g, 7.4 mmols) was combined with isopropyl alcohol to give 1.5 g(79%) of the title compound as a colorless oil.

¹H NMR (CDCl₃) δ: 7.76 (1H, d, J=8.2 Hz), 7.40 (1H, d, J=7.4 Hz), 7.37(1H, dd, J=1.4, 8.2 Hz), 5.23 (1H, septet, J=6.2 Hz), 2.57 (3H, s), 1.37(6H, d, J=6.2 Hz).

4-Bromo-1-(1-isopropoxyvinyl)-2-methyl-benzene (Intermediate 78)

Using General Procedure 1; isopropyl 2-methyl-4-bromobenzoate(Intermediate 77, 800.0 mg, 3.11 mmols) and 6.2 mL of Tebbe's Reagent(885.2 mg, 3.11 mmols) afforded 595.0 mg (75%) of the title compound asa colorless oil after column chromatography (100% hexanes).

¹H NMR (CDCl₃) δ: 7.31-7.25 (2H, m), 7.16 (1H, d, J=8.2 Hz), 4.34 (1H,septet, J=6.0 Hz), 4.31 (1H, d, J=2.1 Hz), 4.18 (1H, d, J=2.1 Hz), 2.33(3H, s), 1.31 (6H, d, J=6.0 Hz).

4-Bromo-1-(1-isopropoxycyclopropyl)-2-methyl-benzene (Intermediate 79)

Using General Procedure 2;4-bromo-1-(1-isopropoxyvinyl)-2-methyl-benzene (Intermediate 78, 389.0mg, 1.53 mmols), Et₂Zn (376.6 mg, 3.05 mmols), and CH₂I₂ (817.0 mg, 3.05mmols) in 3.0 mL Et₂O afforded 340.0 mg (84%) of the title compound as acolorless oil after chromatography (3% EtOAc—hexanes).

¹H NMR (CDCl₃) δ: 7.33 (1H, d, J=2.3 Hz), 7.24 (1H, dd, J=2.3, 8.2 Hz),7.13 (1H, d, J=8.2 Hz), 3.57 (1H, septet, J=6.1 Hz), 2.49 (3H, s), 1.00(2H, mn), 0.97 (6H, d, J=6.1 Hz), 0.82 (2H, m).

[4-(1-Isopropoxycyclopropyl)-3-methyl-phenylethynyl]-trimethylsilane(Intermediate 80)

Using General Procedure D;4-bromo-1-(1-isopropoxycyclopropyl)-2-methyl-benzene (Intermediate 79,250.0 mg, 0.95 mmol) in triethylamine (8 mL) was treated withcopper(I)iodide (19.0 mg, 0.10 mmol) and then sparged with argon for 5minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then addedfollowed by dichlorobis-(triphenylphosphine)palladium(II) (70.0 mg, 0.1mmol). The resulting reaction mixture was heated to 70° C. for 5d. Thetitle compound (250.0 mg, 91%) was isolated by chromatography (0-3%EtOAc—hexanes).

¹H NMR (CDCl₃) δ: 7.32-7.17 (3H, m), 3.56 (1H, septet, J=6.2 Hz), 2.48(3H, s), 1.00 (2H, m), 0.95 (6H, d, J=6.2 Hz), 0.83 (2H, m), 0.24 (9H,s).

4-Ethynyl-1-(1-isopropoxycyclopropyl)-2-methyl-benzene (Intermediate 81)

Using General Procedure E;[4-(1-isopropoxycyclopropyl)-3-methyl-phenylethynyl]-trimethylsilane(Intermediate 80, 250.0 mg, 0.87 mmol) in methanol (10 mL) was treatedwith potassium carbonate (100.0 mg, 0.72 mmol) and stirred overnight atambient temperature. The crude alkyne (180 mg, 98%) was used directly inthe next reaction.

¹H NMR (CDCl₃) δ: 7.32 (1H, s), 7.23 (2H, m), 3.57 (1H, septet, J=6.2Hz), 3.05 (1H, s), 2.50 (3H, s), 1.11 (2H, m), 0.96 (6H, d, J=6.2 Hz),0.83 (2H, m).

Ethyl 4-[4-(1-isopropoxycyclopropyl)-3-methyl-phenylethynyl]-benzoate(Compound 83, General Formula 2)

Using General Procedure F;4-ethynyl-1-(1-isopropoxycyclopropyl)-3-methyl-benzene (Intermediate 81,80.0 mg, 0.13 mmol) and ethyl-4-iodo benzoate (Reagent A, 100.0 mg, 0.36mmol) in triethylamine (5 mL) was treated with copper(I)iodide (25.0 mg,0.13 mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)-palladium(II) (91 mg, 0.13 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-4% EtOAc—hexanes) afforded 75.0 mg(56%) of the title compound as an orange solid.

¹H NMR (CDCl₃) δ: 8.02 (2H, d, J=8.2 Hz), 7.57 (2H, d, J=8.2 Hz), 7.39(1H, s), 7.29-7.20 (2H, m), 4.39 (2H, q, J=7.1 Hz), 3.60 (1H, septet,J=6.2 Hz), 1.40 (3H, t, J=7.1 Hz), 1.13 (2H, m), 0.97 (6H, d, J=6.2 Hz),0.87 (2H, m).

Methyl{4-[4-(1-isopropoxycyclopropyl)-3-methyl-phenylethynyl]-phenyl}-acetate(Compound 84, General Formula 2)

Using General Procedure F;1-ethynyl-4-(1-isopropoxycyclopropyl)-3-methyl-benzene (Intermediate 81,100.0 mg, 0.47 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 129.0mg, 0.45 mmol) in triethylamine (6 mL) was treated with copper(I)iodide(30.0 mg, 0.16 mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)palladium(II) (110 mg, 0.16 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-4% EtOAc—hexanes) afforded 120.0mg (71%) of the title compound.

hu 1H NMR (CDCl₃) δ: 7.48 (2H, d, J=8.5 Hz), 7.36 (1H, s), 7.29-7.22(4H, m 3.70 (3H, s), 3.63 (2H, s), 3.60 (1H, septet, J=6.2 Hz), 2.52(3H, s), 1.09 (2H, m), 0.97 (6H, d, J=6.2 Hz), 0.86 (2H, m).

4-[4-(1-Isopropoxycyclopropyl)-3-methyl-phenylethynyl]-benzoic acid(Compound 85, General Formula 2)

Using General Procedure I; a solution of ethyl4-[4-(1-isopropoxycyclopropyl)-3-methyl-phenylethynyl]-benzoate(Compound 83, 60.0 mg, 0.17 mmol) in ethanol (2 mL) and tetrahydrofuran(2 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueoussolution) and stirred overnight at room temperature. Work-up afforded38.0 mg (69%) of the title compound as a colorless solid.

¹H NMR (d₆-acetone) δ: 8.06 (2H, d, J=8.5 Hz), 7.66 (2H, d, J=8.5 Hz),7.42 (1H, s), 7.35 (2H, m), 3.59 (1H, septet, J=6.2 Hz), 2.52 (3H, s),1.07 (2H, m), 0.93 (6H, d, J=6.2 Hz), 0.88 (2H, m).

{4-[4-(1-Isopropoxycyclopropyl)-3-methyl-phenylethynyl]-phenyl}-aceticacid (Compound 86, General Formula 2)

Using General Procedure I; a solution ofmethyl{4-[4-(1-isopropoxycyclopropyl)-3-methyl-phenylethynyl]-phenyl}-acetate(Compound 84, 100.0 mg, 0.28 mmol) in ethanol (3 mL) and tetrahydrofuran(3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1Naqueous solution) and stirred overnight at room temperature. Work-upafforded 60.0 mg (62%) of the title compound as a colorless solid.

¹H NMR (CDCl₃) δ: 7.48 (2H, d, J=7.6 Hz), 7.36 (1H, s), 7.25 (4H, m),3.65 (2H, s), 3.60 (1H, septet, J=6.2 Hz), 2.51 (3H, s), 1.12 (2H, m),0.97 (6H, d, J=6.2 Hz), 0.86 (2H, m).

2,2-Dimethylpropyl 2-methyl-4-bromobenzoate (Intermediate 82)

Using General Esterification Method C; 2-methyl-4-bromo-benzoic acid(1.82 g, 8.47 mmols) was refluxed for 3 h with 10 mL SOCl₂. Theresulting solution was concentrated under reduced pressure and the crudeacyl chloride combined with 2,2-dimethylpropanol (0.75 g, 8.47 mmols)and pyridine (1.4 mL, 16.9 mmols) to give the title compound (1.64 g,68%) after work-up and column chromatography (2-5% EtOAc—hexanes) as acolorless oil.

¹H NMR (CDCl₃) δ: 7.81 (1H, d, J=8.2 Hz), 7.42 (1H, d, J=2.0 Hz), 7.39(1H, dd, J=2.0, 8.2 Hz), 3.99 (2H, s), 2.60 (3H, s), 1.03 (9H, s).

4-Bromo-1-[1-(2,2-dimethylpropyloxy)-vinyl]-2-methyl-benzene(Intermediate 83)

Using General Procedure 1; 2,2-dimethylpropyl 2-methyl-4-bromobenzoate(Intermediate 82, 820.0 mg, 2.87 mmols) and 5.8 mL of Tebbe's Reagent(817.0 mg, 2.87 mmols) afforded 800.0 mg (98%) of the title compound asa colorless oil after column chromatography (100% hexanes).

¹H NMR (CDCl₃) δ: 7.32 (1H, d, J=2.0 Hz), 7.28 (1H, dd, J=2.0, 8.2 Hz),7.18 (1H, d, J=8.2 Hz), 4.27 (1H, d, J=2.1 Hz), 4.10 (1H, d, J=2.1 Hz),3.43 (2H, s), 2.33 (3H, s), 0.98 (9H, s).

4-Bromo-1-[1-(2,2-dimethylpropyloxy)-cyclopropyl]-2-methyl-benzene(Intermediate 84)

Using General Procedure 2;4-bromo-1-[1-(2,2-dimethylpropyloxy)-cyclopropyl]-2-methyl-benzene(Intermediate 83, 400.0 mg, 1.43 mmols), Et₂Zn (353.2 mg, 2.86 mmols),and CH₂I₂ (760.0 mg, 2.86 mmols) in 3.0 mL Et₂O afforded 370.0 mg (87%)of the title compound as a colorless oil after chromatography (3%EtOAc—hexanes).

¹H NMR (CDCl₃) δ: 7.36 (1H, s), 7.27 (1H, d, J=8.5 Hz), 7.09 (1H, d,J=7.9 Hz), 2.86 (2H, s), 2.52 (3H, s), 1.08 (2H, m), 0.83 (2H, m), 0.80(9H, s)

[4-[1-[1-(2,2-Dimethylpropyloxy)-cyclopropyl]-3-methyl-phenylethynyl]]-trimethylsilane(Intermediate 84a)

Using General Procedure D;4-bromo-1-[1-(2,2-dimethylpropyloxy)-cyclopropyl]-2-methyl-benzene(Intermediate 84, 255.0 mg, 0.86 mmol) in triethylamine (8 mL) wastreated with copper(I)iodide (17.0 mg, 0.09 mmol) and then sparged withargon for 5 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) wasthen added followed by dichlorobis-(triphenylphosphine)palladium(II)(63.0 mg, 0.09 mmol). The resulting reaction mixture was heated to 70°C. for 5d. The title compound (220.0 mg, 81%) was isolated bychromatography (1-2% EtOAc—hexanes).

¹H NMR (CDCl₃) δ: 7.30 (1H, s), 7.21 (1H, d, J=7.6 Hz), 7.12 (1H, d,J=8.6 Hz), 2.80 (2H, s), 2.47 (3H, s), 1.05 (2H, m), 0.82 (2H, m), 0.75(9H, s), 0.24 (9H, s).

4-Ethynyl-1-[1-(2,2-dimethylpropyloxy)-cyclopropyl]-2-methyl-benzene(Intermediate 85)

Using General Procedure E;[4-[1-[1-(2,2-dimethylpropyloxy)-cyclopropyl]]-3-methyl-phenylethynyl]-trimethylsilane(Intermediate 84a, 220.0 mg, 0.83 mmol) in methanol (10 mL) was treatedwith potassium carbonate (80.0 mg, 0.58 mmol) and stirred overnight atambient temperature. The crude alkyne (155 mg, 76%) was used directly inthe next reaction.

¹H NMR (CDCl₃) δ: 7.32 (1H, s), 7.24 (1H, d, J=7.1 Hz), 7.15 (1H, d,J=7.1 Hz), 3.04 (1H, s), 2.83 (2H, s), 2.49 (3H, s), 1.06 (2H, m), 0.83(2H, m), 0.76 (9H, s).

Ethyl4-[4-[1-(2,2-dimethylpropyloxy)-cyclopropyl]-3-methyl-phenylethynyl]-benzoate(Compound 87, General Formula 2)

Using General Procedure F;4-ethynyl-1-[1-(2,2-dimethylpropyloxy)-cyclopropyl]-3-methyl-benzene(Intermediate 85, 75.0 mg, 0.3 mmol) and ethyl-4-iodo benzoate (ReagentA, 86.0 mg, 0.31 mmol) in triethylamine (5 mL) was treated withcopper(I)iodide (21.0 mg, 0.11 mmol) and sparged with argon for 5minutes. Dichlorobis(triphenylphosphine)-palladium(II) (78 mg, 0.11mmol) was added and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-4% EtOAc—hexanes) afforded 60.0 mg(50%) of the title compound as an orange solid.

¹H NMR (CDCl₃) δ: 8.02 (2H, d, J=8.4 Hz), 7.56 (2H, d, J=8.4 Hz), 7.38(1H, s), 7.30 (1H, dd, J=1.1, 8.0 Hz), 7.20 (1H, d, J=8.0 Hz), 4.38 (2H,q, J=7.1 Hz), 2.84 (2H, s), 2.52 (3H, s), 1.40 (3H, t, J=7.1 Hz), 1.07(2H, m), 0.84 (2H, m), 0.77 (9H, s).

Methyl{4-[4-[1-(2,2-dimethylpropyloxy)-cyclopropyl]-3-methyl-phenylethynyl]-phenyl}-acetate(Compound 88, General Formula 2)

Using General Procedure F;4-ethynyl-1-[1-(2,2-dimethylpropyloxy)-cyclopropyl]-3-methyl-benzene(Intermediate 85, 75.0 mg, 0.31 mmol) and methyl-(4-iodophenyl)-acetate(Reagent B, 86.0 mg, 0.31 mmol) in triethylamine (6 mL) was treated withcopper(I)iodide (21.0 mg, 0.11 mmol) and sparged with argon for 5minutes.

Dichlorobis(triphenylphosphine)palladium(II) (78 mg, 0.11 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-4% EtOAc—hexanes) afforded 100.0mg (83%) of the title compound.

¹H NMR (CDCl₃) δ: 7.48 (2H, d, J=7.9 Hz), 7.36-7.24 (4H, m), 7.18 (1H,d, J=7.9 Hz), 3.70 (3H, s), 3.63 (2H, s), 2.84 (2H, s), 2.51 (3H, s),1.07 (2H, m), 0.83 (2H, m), 0.77 (9H, s).

4-[4-[1-(2,2-Dimethylpropyloxy)-cyclopropyl]-3-methyl-phenylethynyl]-benzoicacid (Compound 89, General Formula 2)

Using General Procedure I; a solution of ethyl4-[4-[1-(2,2-dimethylpropyloxy)-cyclopropyl]-3-methyl-phenylethynyl]-benzoate(Compound 87, 60.0 mg, 0.15 mmol) in ethanol (3 mL) and tetrahydrofuran(3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1Naqueous solution) and stirred overnight at room temperature. Work-upafforded 24.0 mg (43%) of the title compound as a colorless solid.

¹H NMR (CDCl₃) δ: 8.06 (2H, d, J=7.9 Hz), 7.65 (2H, d, J=7.9 Hz), 7.42(1H, s), 7.33 (2H, m), 2.89 (2H, s), 2.53 (3H, s), 1.07 (2H, m), 0.90(2H, m), 0.77 (9H, s).

{4-[4-[1-(2,2-Dimethylpropyloxy)-cyclopropyl]-3-methyl-phenylethynyl]-phenyl}-aceticacid (Compound 90, General Formula 2)

Using General Procedure I; a solution ofmethyl{4-[4-[1-(2,2-dimethylpropyloxy)-cyclopropyl]-3-methyl-phenylethynyl]-phenyl}-acetate(Compound 88, 95.0 mg, 0.24 mmol) in ethanol (3 mL) and tetrahydrofuran(3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1Naqueous solution) and stirred overnight at room temperature. Work-upafforded 49.0 mg (53%) of the title compound as a colorless solid.

¹H NMR (CDCl₃) δ: 7.49 (2H, d, J=8.2 Hz), 7.36 (1H, s), 7.27 (3H, m),7.18 (1H, d, J=7.9 Hz), 3.66 (2H, s), 2.84 (2H, s), 2.51 (3H, s), 1.07(2H, m), 0.83 (2H, m), 0.77 (9H, s).

Benzyl 4-bromo-2-ethyl-benzoate (Intermediate 86)

Using General Esterification Method B; 4-bromo-2-ethyl-benzoic acid(0.98 g, 4.25 mmols), benzyl bromide (0.80 g, 4.68 mmols), and K₂CO₃(0.64 g, 4.68 mmols) afforded 1.0 g (74%) of the title compound aftercolumn chromatography (0-3% EtOAc—hexanes).

¹H NMR (CDCl₃) δ: 7.76 (1H, d, J=8.5 Hz), 7.41-7.33 (7H, m), 5.32 (2H,s), 2.95 (2H, q, J=7.6 Hz), 1.20 (3H, t, J=7.6 Hz).

4-Bromo-1-(1-benzyloxyvinyl)-2-ethyl-benzene (Intermediate 87)

Using General Procedure 1; benzyl 4-bromo-2-ethylbenzoate (Intermediate86, 1.20 g, 3.78 mmols) and 7.6 mL of Tebbe's Reagent (1.08 g, 3.78mmols) afforded 800.0 mg (66%) of the title compound after columnchromatography (100% hexanes).

¹H NMR (CDCl₃) δ: 7.37-7.17 (8H, m), 4.88 (2H, s), 4.43 (1H, d, J=2.1Hz), 4.25 (1H, d, J=2.1 Hz), 2.71 (2H, q, J=7.6 Hz), 1.18 (3H, t, J=7.6Hz).

4-Bromo-1-(1-benzyloxycyclopropyl)-2-ethyl-benzene (Intermediate 88)

Using General Procedure 2; 4-bromo-1-(1-benzyloxyvinyl)-2-ethyl-benzene(Intermediate 87, 330. 0 mg, 1.04 mmols), Et₂Zn (257.0 mg, 2.08 mmols),and CH₂I₂ (557.0 mg, 2.08 mmols) in 4 mL Et₂O afforded 241.0 mg (70%) ofthe title compound as a colorless oil after chromatography (2-5%EtOAc—hexanes).

¹H NMR (CDCl₃) δ: 7.43-7.15 (8H, m), 4.27 (2H, s), 3.00 (2H, q, J=7.6Hz), 1.29-1.21 (5H, m), 0.90 (2H, m).

[4-(1-Benzyloxycyclopropyl)-3-ethyl-phenylethynyl]-trimethylsilane(Intermediate 89)

Using General Procedure D;4-bromo-1-(1-benzyloxycyclopropyl)-2-ethyl-benzene (Intermediate 88,220.0 mg, 0.66 mmol) in triethylamine (8 mL) was treated withcopper(I)iodide (14.0 mg, 0.07 mmol) and then sparged with argon for 5minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then addedfollowed by dichlorobis-(triphenylphosphine)palladium(II) (50.0 mg, 0.07mmol). The resulting reaction mixture was heated to 70° C. for 5d. Thetitle compound was isolated by chromatography (0-2% EtOAc—hexanes).

¹H NMR (CDCl₃) δ: 7.41-7.13 (8H, m), 4.24 (2H, s), 2.98 (2H, q, J=7.6Hz), 1.25 (3H, t, J=7.6 Hz), 1.20 (2H, m), 0.90 (2H, m), 0.26 (9H, s).

4-Ethynyl-1-(1-benzyloxycyclopropyl)-2-ethyl-benzene (Intermediate 90)

Using General Procedure E;[4-(1-benzyloxycyclopropyl)-3-ethyl-phenylethynyl]-trimethylsilane(Intermediate 89, 240 mg, 0.69 mmol) in methanol (6 mL) was treated withpotassium carbonate (10.0 mg, 0.72 mmol) and stirred overnight atambient temperature. The crude alkyne (190 mg, 99%) was used directly inthe next reaction. ¹H NMR (CDCl₃) δ: 7.43-7.15 (8H, m), 4.27 (2H, s),3.08 (1H, s), 3.01 (2H, q, J=7.6 Hz), 1.26 (3H, t, J=7.6 Hz), 1.22 (2H,m), 0.92 (2H, m).

Ethyl 4-[4-(1-benzyloxycyclopropyl)-3-ethyl-phenylethynyl]-benzoate(Compound 91, General Formula 2)

Using General Procedure F;1-ethynyl-4-(1-benzyloxycyclopropyl)-3-ethyl-benzene (Intermediate 90,90.0 mg, 0.33 mmol) and ethyl-4-iodo benzoate (Reagent A, 100.0 mg, 0.36mmol) in triethylamine (5 mL) was treated with copper(I)iodide (21.0 mg,0.11 mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)palladium(II) (77 mg, 0.11 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-4% EtOAc—hexanes) afforded 100.0mg (72%) of the title compound.

¹H NMR (CDCl₃) δ: 8.03 (2H, d, J=7.9 Hz), 7.59 (2H, d, J=7.9 Hz), 7.49(1H, s), 7.36-7.16 (7H, m), 4.38 (2H, q, J=7.1 Hz), 4.28 (2H, s), 3.04(2H, q, J=7.6 Hz), 1.40 (3H, t, J=7.1 Hz), 1.29 (3H, t, J=7.6 Hz), 1.23(2H, m), 0.94 (2H, m).

Methyl{4-[4-(1-benzyloxycyclopropyl)-3-ethyl-phenylethynyl]-phenyl}-acetate(Compound 92, General Formula 2)

Using General Procedure F;1-ethynyl-4-(1-benzyloxycyclopropyl)-3-ethyl-benzene (Intermediate 90,107.0 mg, 0.39 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 110.0mg, 0.39 mmol) in triethylamine (5 mL) was treated with copper(I)iodide(25.0 mg, 0.13 mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)palladium(II) (91 mg, 0.13 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-4% EtOAc—hexanes) afforded 130.0mg (79%) of the title compound as a pale-yellow oil.

¹H NMR (CDCl₃) δ: 7.49 (3H, m), 7.32-7.16 (9H, m), 4.28 (2H, s), 3.71(3H, s), 3.64 (2H, s), 3.03 (2H, q, J=7.6 Hz), 1.32-1.23 (5H, m), 0.94(2H, m).

4-[4-(1-Benzyloxycyclopropyl)-3-ethyl-phenylethynyl]-benzoic acid(Compound 93, General Formula 2)

Using General Procedure I; a solution of ethyl4-[4-(1-benzyloxycyclopropyl)-3-ethyl-phenylethynyl]-benzoate (Compound91, 100.0 mg, 0.24 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL)was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueoussolution) and stirred overnight at room temperature. Work-up andpurification by HPLC (Partisil 10-pac, 10% H₂O/CH₃CN) afforded the titlecompound as a colorless solid.

¹H NMR (CDCl₃) δ: 8.10 (2H, d, J=8.5 Hz), 7.64 (2H, d, J=8.5 Hz), 7.50(1H, s), 7.35-7.16 (7H, m), 4.29 (2H, s), 3.04 (2H, q, J=7.6 Hz), 1.30(3H, t, J=7.6 Hz), 1.25 (2H, m), 0.95 (2H, m).

{4-[4-(1-Benzyloxycyclopropyl)-3-ethyl-phenylethynyl]-phenyl}-aceticacid (Compound 94, General Formula 2)

Using General Procedure I; a solution ofmethyl{4-[4-(1-benzyloxycyclopropyl)-3-ethyl-phenylethynyl]-phenyl}-acetate(Compound 92, 130.0 mg, 0.31 mmol) in ethanol (3 mL) and tetrahydrofuran(3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1Naqueous solution) and stirred overnight at room temperature. Work-up andpurification by HPLC (Partisil 10-pac, 10% H₂O/CH₃CN) afforded the titlecompound.

¹H NMR (CDCl₃) δ: 7.49 (3H, m), 7.31-7.16 (9H, m), 4.28 (2H, s), 3.66(2H, s), 3.02 (2H, q, J=7.6 Hz), 1.29 (3H, t, J=7.6 Hz), 1.23 (2H, m),0.94 (2H, m).

Isopropyl 2-ethyl-4-bromobenzoate (Intermediate 91)

Using General Esterification Procedure A; 4-bromo-2-ethyl-benzoic acid(2.25 g, 9.9 mmols) was combined with isopropyl alcohol to give thetitle compound as a colorless oil after column chromatography (2%EtOAc—hexanes).

¹H NMR (CDCl₃) δ: 7.69 (1H, d, J=8.5 Hz), 7.41 (1H, s), 7.36 (1H, d,J=8.5 Hz), 5.23 (1H, septet, J=6.2 Hz), 2.95 (2H, q, J=7.6 Hz), 1.37(6H, d, J=6.2 Hz), 1.23 (3H, t, J=7.6 Hz).

4-Bromo-1-(1-isopropoxyvinyl)-2-ethyl-benzene (Intermediate 92)

Using General Procedure 1; isopropyl 2-ethyl-4-bromobenzoate(Intermediate 91, 1.21 g, 4.46 mmols) and 8.9 mL of Tebbe's Reagent(1.27 g, 4.46 mmols) afforded 570.0 mg (75%) of the title compound aftercolumn chromatography (100% hexanes).

¹H NMR (CDCl₃) δ: 7.36 (1H, d, J=2.0 Hz), 7.28 (1H, dd, J=2.0, 8.0 Hz),7.17 (1H, d, J=8.0 Hz), 4.39 (1H, septet, J=6.2 Hz), 4.31 (1H, d, J=2.1Hz), 4.26 (1H, d, J=2.1 Hz), 2.73 (2H, q, J=7.6 Hz), 1.35 (6H, d, J=6.2Hz), 1.24 (3H, t, J=7.6 Hz).

4-Bromo-1-(1-isopropoxycyclopropyl)-2-ethyl-benzene (Intermediate 93)

Using General Procedure 2; 4-bromo-1-(1-isopropoxyvinyl)-2-ethyl-benzene(Intermediate 92, 570.0 mg, 2.11 mmols), Et₂Zn (521.0 mg, 4.22 mmols),and CH₂I₂ (1.13 g, 4.22 mmols) in 7.0 mL Et₂O afforded 500.0 mg (85%) ofthe title compound as a colorless oil after chromatography (3%EtOAc—hexanes).

¹H NMR (CDCl₃) δ: 7.39 (1H, d, J=2.1 Hz), 7.25 (1H, dd, J=2.1, 8.1 Hz),7.15 (1H, d, J=8.1 Hz), 3.59 (1H, septet, J=6.2 Hz), 2.97 (2H, q, J=7.6Hz), 1.27 (3H, t, J=7.6 Hz), 1.11 (2H, m), 0.97 (6H, d, J=6.2 Hz), 0.83(2H, m).

[4-(1-Isopropoxycyclopropyl)-3-ethyl-phenylethynyl]-trimethylsilane(Intermediate 94)

Using General Procedure D;4-bromo-1-(1-isopropoxycyclopropyl)-2-ethyl-benzene (Intermediate 93,300.0 mg, 1.07 mmol) in triethylamine 8 mL) was treated withcopper(I)iodide (20.0 mg, 0.11 mmol) and then sparged with argon for 5minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then addedfollowed by dichlorobis-(triphenylphosphine)palladium(II) (75.0 mg, 0.11mmol). The resulting reaction mixture was heated to 70° C. for 5d. Thetitle compound (320.0 mg, 99%) was isolated by chromatography (0-2%EtOAc—hexanes) as an orange oil.

¹H NMR (CDCl₃) δ: 7.37-7.21 (3H, m), 3.56 (1H, septet, J=6.2 Hz), 2.96(2H, q, J=7.6 Hz), 1.27 (3H, t, J=7.6 Hz), 1.10 (2H, m), 0.94 (6H, d,J=6.2 Hz), 0.84 (2H, m), 0.25 (9H, s).

4-Ethynyl-1-(1-isopropoxycyclopropyl)-2-ethyl-benzene (Intermediate 95)

Using General Procedure E;[4-(1-isopropoxycyclopropyl)-3-ethyl-phenylethynyl]-trimethylsilane(Intermediate 94, 330.0 mg, 1.10 mmols) in methanol (10 mL) was treatedwith potassium carbonate (150.0 mg, 1.10 mmol) and stirred overnight atambient temperature. The crude alkyne (238 mg, 95%) was used directly inthe next reaction.

¹H NMR (CDCl₃) δ: 7.40-7.22 (3H, m), 3.59 (1H, septet, J=6.2 Hz), 3.07(1H, s), 2.97 (2H, q, J=7.6 Hz), 1.28 (3H, t, J=7.6 Hz), 1.12 (2H, m),0.96 (6H, d, J=6.2 Hz), 0.85 (2H, m).

Ethyl 4-[4-(1-isopropoxycyclopropyl)-3-ethyl-phenylethynyl]-benzoate(Compound 95, General Formula 2)

Using General Procedure F;4-ethynyl-1-(1-isopropoxycyclopropyl)-3-ethyl-benzene (Intermediate 95,108.0 mg, 0.47 mmol) and ethyl-4-iodo benzoate (Reagent A, 130.0 mg, 047mmol) in triethylamine (5 mL) was treated with copper(I)iodide (30.0 mg,0.16 mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)-palladium(II) (110 mg, 0.16 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-4% EtOAc—hexanes) afforded 125.0mg (71%) of the title compound as an oil.

¹H NMR (CDCl₃) δ: 8.02 (2H, d, J=8.2 Hz), 7.59 (2H, d, J=8.2 Hz), 7.46(1H, s), 7.33-7.26 (2H, m), 4.39 (2H, q, J=7.1 Hz), 3.62 (1H, septet,J=6.2 Hz), 3.01 (2H, q, J=7.6 Hz), 1.41 (3H, t, J=7.1 Hz), 1.31 (3H, t,J=7.1 Hz), 1.14 (2H, m), 0.97 (6H, d, J=6.2 Hz), 0.88 (2H, m).

Methyl{4-[4-(1-isopropoxycyclopropyl)-3-ethyl-phenylethynyl]-phenyl}-acetate(Compound 96, General Formula 2)

Using General Procedure F;1-ethynyl-4-(1-isopropoxycyclopropyl)-3-ethyl-benzene (Intermediate 95,130.0 mg, 0.57 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 157.0mg, 0.57 mmol) in triethylamine (5 mL) was treated with copper(I)iodide(36.0 mg, 0.19 mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)palladium(II) (133 mg, 0.19 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-5% EtOAc—hexanes) afforded 150.0mg (70%) of the title compound as an orange oil.

¹H NMR (CDCl₃) δ: 7.50-7.44 (3H, m), 7.27 (4H, m), 3.70 (3H, s), 3.64(2H, s), 3.62 (1H, septet, J=6.2 Hz), 3.00 (2H, q, J=7.6 Hz), 1.30 (3H,t, J=7.6 Hz), 1.13 (2H, m), 0.97 (6H, d, J=6.2 Hz), 0.87 (2H, m).

4-[4-(1-Isopropoxycyclopropyl)-3-ethyl-phenylethynyl]-benzoic acid(Compound 97, General Formula 2)

Using General Procedure I; a solution of ethyl4-[4-(1-isopropoxycyclopropyl)-3-ethyl-phenylethynyl]-benzoate (Compound95, 110.0 mg, 0.29 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL)was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueoussolution) and stirred overnight at room temperature. Work-up andisolation by HPLC (partisil 10-pac, 10% H₂O/CH₃CN) afforded the titlecompound as a colorless solid.

¹H NMR (d₆-acetone) δ: 8.06 (2H, d, J=8.2 Hz), 7.67 (2H, d, J=8.2 Hz),7.49 (1H, s), 7.40-7.34 (2H, m), 3.61 (1H, septet, J=6.2 Hz), 3.01 (2H,q, J=7.6 Hz), 1.29 (3H, t, J=7.6 Hz), 1.08 (2H, m), 0.93 (6H, d, J=6.2Hz), 0.88 (2H, m).

{4-[4-(1-Isopropoxycyclopropyl)-3-ethyl-phenylethynyl]-phenyl}-aceticacid (Compound 98, General Formula 2)

Using General Procedure I; a solution ofmethyl{4-[4-(1-isopropoxycyclopropyl)-3-ethyl-phenylethynyl]-phenyl}-acetate(Compound 96, 156.0 mg, 0.41 mmol) in ethanol (3 mL) and tetrahydrofuran(3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1Naqueous solution) and stirred overnight at room temperature. Work-up andisolation by HPLC (partisil 10-pac, 10% H₂O/CH₃CN) afforded 85.0 mg(57%) of the title compound.

¹H NMR (CDCl₃) δ: 7.54-7.48 (3H, m), 7.34-7.27 (4H, m), 3.68 (2H, s),3.66 (1H, septet, J=6.2 Hz), 3.03 (2H, q, J=7.6 Hz), 1.33 (2H, t, J=7.6Hz), 1.17 (2H, m), 1.01 (6H, d, J=6.2 Hz), 0.90 (2H, m).

(4-Bromo-3-isopropyl-phenoxy)-triisopropyl-silane (Intermediate 96)

To a solution of 4-bromo-3-isopropylphenol (880.0 mg, 4.09 mmols) andimidazole (417.0 mg, 6.13 mmols) in 10 mL DMF was addedchloro-triisopropylsilane (946.0 mg, 4.90 mmols). After stirringovernight at room temperature the solution was diluted with H₂O andextracted with EtOAc. The combined organic layers were washed with H₂Oand saturated aqueous NaCl before being dried (MgSO₄) and concentratedunder reduced pressure. The title compound, 1.30 g (92%), was isolatedby column chromatography (1-2% EtOAc—hexanes) as a colorless oil.

¹H NMR (CDCl₃) δ: 7.34 (1H, d, J=8.5 Hz), 6.81 (1H, d, J=2.9 Hz), 6.59(1H, dd, J=2.9, 8.5 Hz), 3.31 (1H, septet, J=7.0 Hz), 1.33-1.21 (3H, m),1.24 (6H, d, J=7.0 Hz), 1.13 (18H, d, J=7.0 Hz).

Ethyl 2-isopropyl-4-triisopropylsilanyloxy-benzoate (Intermediate 97)

To a solution of (4-bromo-3-isopropyl-phenoxy)-triisopropyl-silane(Intermediate 96, 1.3 g, 3.8 mmols) in 15 mL Et₂O cooled to −78° C. wasadded 4.9 mL of tert-butyllithium in pentane (532.0 mg, 8.3 mmols; 1.7M). After stirring for 30 minutes ethyl chloroformate (832.0 mg, 7.8mmols) was added. The resulting solution was warmed to room temperatureand quenched by the addition of saturated aqueous NH₄Cl. The mixture wasextracted with EtOAc and the combined organic layers dried (MgSO₄)concentrated under reduced pressure and the residue chromatographed (4%EtOAc—hexanes) to give 1.09 g (85%) of the title compound as a colorlessoil.

¹H NMR (CDCl₃) δ: 7.72 (1H, d, J=8.5 Hz), 6.87 (1H, d, J=2.3 Hz), 6.69(1H, dd, J=2.3, 8.5 Hz), 3.88 (1H, septet; J=7.1 Hz), 4.30 (2H, q, J=7.1Hz), 1.36 (3H, t, J=7.1 Hz), 1.31-1.17 (9H, m), 1.09 (18H).

[4-(1-Ethoxyvinyl)-3-isopropyl-phenoxy]-triisopropyl-silane(Intermediate 98)

Using General Procedure 1; ethyl2-isopropyl-4-triisopropylsilanyloxy-benzoate (Intermediate 97, 450.0mg, 1.34 mmols) and 2.0 mL of Tebbe's Reagent (398.0 mg, 1.40 mmols)afforded the title compound after column chromatography (100% hexanes).

¹H NMR (CDCl₃) δ: 7.11 (1H, d, J=8.2 Hz), 6.78 (1H, d, J=2.3 Hz), 6.63(1H, dd, J=2.3, 8.2 Hz), 4.23 (1H, d, J=1.7 Hz), 4.10 (1H, d, J=1.7 Hz),3.86 (2H, q, J=7.0 Hz), 3.16 (1H, septet, J=7.0 Hz), 1.35 (3H, t, J=7.1Hz), 1.28-1.19 (3H, m), 1.19 (6H, d, J=7.0 Hz), 1.11 (18H).

[4-(1-Ethoxycyclopropyl)-3-isopropyl-phenoxy]-triisopropyl-silane(Intermediate 99)

Using General Procedure 2;[4-(1-ethoxyvinyl)-3-isopropyl-phenoxy]-triisopropyl-silane(Intermediate 98, 300.0 mg, 0.83 mmols), Et₂Zn (325.0 mg, 2.63 mmols),and CH₂I₂ (704.0 mg, 2.63 mmols) in 5.0 mL Et₂O afforded 270.0 mg (86%)of the title compound as a colorless oil after chromatography (0.5-2.5%EtOAc—hexanes).

¹H NMR (CDCl₃) δ: 7.06 (1H, d, J=8.2 Hz), 6.81 (1H, d, J=2.6 Hz), 6.59(1H, dd, J=2.6, 8.2 Hz), 3.76 (1H, septet, J=7.0 Hz), 3.25 (2H, q, J=7.0Hz), 1.30-1.20 (3H, m), 1.19 (6H, d, J=7.0 Hz), 1.15 (2H, m), 1.10(18H), 1.02 (2H, t, J=7.0 Hz), 0.82 (2H, m).

4-(1-Ethoxycyclopropyl)-3-isopropyl-phenol (Intermediate 100)

To a solution of[4-(1-ethoxycyclopropyl)-3-isopropyl-phenoxy]-triisopropyl-silane(Intermediate 99, 360.0 mg, 0.96 mmol) in 3 mL THF at 0° C. was addedtetrabutylammonium fluoride (625.0 mg, 2.39 mmols, 2.4 mL of a 1 Msolution in THF). The solution was stirred at 0° C. for 30 minutes andthen quenched by the addition of H₂O. The mixture was extracted withEtOAc and the combined organic layers were washed with H₂O and saturatedaqueous NaCl before being dried (MgSO₄) and concentrated under reducedpressure. The title compound (180 mg, 86%) was isolated from the residueby column chromatography (4-10% EtOAc—hexanes) as a colorless solid.

¹H NMR (CDCl₃) δ: 7.13 (1H, d, J=8.2 Hz), 6.79 (1H, d, J=2.6H), 6.57(1H, dd, J=2.6, 8.2 Hz), 5.48 (1H, s), 3.79 (1H, septet, J=7.0 Hz), 3.32(2H, q, J=7.0 Hz), 1.21 (6H, d, J=7.0 Hz), 1.12 (2H, m), 1.05 (3H, t,J=7.0 Hz), 0.84 (2H, m).

4-(1-Ethoxycyclopropyl)-3-isopropyl-phenyl1,1,1-trifluoromethansulfonate (Intermediate 101)

A solution of 4-(1-ethoxycyclopropyl)-3-isopropyl-phenol (Intermediate100, 172.0 mg, 0.78 mmol) in 5 mL of CH₂Cl₂ was cooled to 0° C. and toit was added 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine(321.0 mg, 0.82 mmol) and triethylamine (240.0 mg, 2.4 mmols). Theresulting solution was warmed to room temperature and stirred overnight.The reaction was quenched by the addition of H₂O and the mixtureextracted with EtOAc and the combined organic layers were washed with10% aqueous HCl, saturated aqueous NaHCO₃, H₂O, and saturated aqueousNaCl. The solution was dried (MgSO₄) and concentrated under reducedpressure. The title compound was isolated by column chromatography (2-4%EtOAc—hexanes) as a colorless oil, 240.0 mg, 87%.

¹H NMR (CDCl₃) δ: 7.31 (1H, d, J=8.6 Hz), 7.18 (1H, d, J=2.6 Hz), 7.00(1H, dd, J=2.6, 8.6 Hz), 3.87 (1H, septet, J=7.0 Hz), 2.38 (2H, q, J=7.0Hz), 1.24 (6H, d, J=7.0 Hz), 1.15 (2H, m), 1.04 (3H, t, J=7.0 Hz), 0.86(2H, m).

[4-(1-Ethoxycyclopropyl)-3-isopropyl-phenylethynyl]-trimethylsilane(Intermediate 102)

Using General Procedure D; 4-(1-ethoxycyclopropyl)-3-isopropyl-phenyl1,1,1-trifluoromethansulfonate (Intermediate 101, 240.0 mg, 0.68 mmol)in triethylamine (2 mL) and DMF (6 mL) was sparged with argon for 5minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then addedfollowed by dichlorobis-(triphenylphosphine)palladium(II) (38.0 mg, 0.05mmol). The resulting reaction mixture was heated to 95° C. for 5d. Thetitle compound, 200.0 mg (99%), was isolated by chromatography (0-2%EtOAc—hexanes) as an orange oil.

¹H NMR (CDCl₃) δ: 7.43 (1H, d, J=1.7 Hz), 7.25 (1H, dd, J=1.7, 7.9 Hz),7.16 (1H, d, J=7.9 Hz), 3.80 (1H, septet, J=6.8 Hz), 3.26 (2H, q, J=7.0Hz), 1.24 (6H, d, J=6.8 Hz), 1.24-1.10 (2H, m), 1.03 (3H, t, J=7.0 Hz),0.87 (2H, s), 0.26 (9H, s).

1-(1-Ethoxycyclopropyl)-4-ethynyl-2-isopropylbenzene (Intermediate 103)

Using General Procedure E;[4-(1-ethoxycyclopropyl)-3-isopropyl-phenylethynyl]-trimethylsilane(Intermediate 102, 210.0 mg, 0.70 mmol) in methanol (10 mL) was treatedwith potassium carbonate (100.0 mg, 0.72 mmol) and stirred overnight atambient temperature. The crude alkyne was used directly in the nextreaction.

¹H NMR (CDCl₃) δ: 7.47 (1H, d, J=1.7 Hz), 7.23 (1H, dd, J=1.7, 7.6 Hz),7.19 (1H, d, J=7.6 Hz), 3.80 (1H, septet, J=7.0 Hz), 3.27 (1H, q, J=7.0Hz), 3.07 (1H, s), 1.23 (6H, d, J=7.0 Hz), 1.13 (2H, m), 1.03 (3H, t,J=7.0 Hz), 0.85 (2H, m).

Ethyl 4-[4-(1-ethoxycyclopropyl)-3-isopropyl-phenylethynyl]-benzoate(Compound 99, General Formula 2)

Using General Procedure F;1-(1-ethoxycyclopropyl)-4-ethynyl-2-isopropylbenzene (Intermediate 103,50.0 mg, 0.22 mmol) and ethyl-4-iodo benzoate (Reagent A, 60.0 mg, 0.22mmol) in triethylamine (5 mL) was treated with copper(I)iodide (14.0 mg,0.07 mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)-palladium(II) (51 mg, 0.07 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (1-2% EtOAc—hexanes) afforded 28.0 mg(34%) of the title compound.

¹H NMR (CDCl₃) δ: 8.01 (2H, d, J=8.2 Hz), 7.59 (2H, d, J=8.2 Hz), 7.51(1H, d, J=1.7 Hz), 7.28 (1H, dd, J=1.7, 7.9 Hz), 7.21 (1H, d, J=7.9 Hz),4.38 (2H, q, J=7.1 Hz), 3.83 (1H, septet, J=6.7 Hz), 3.29 (2H, q, J=7.0Hz), 1.40 (3H, t, J=7.1 Hz), 1.26 (6H, d, J=6.7 Hz), 1.14 (2H, m), 1.04(3H, t, J=7.0 Hz), 0.87 (2H, m).

Methyl{4-[4-(1-ethoxycyclopropyl)-3-isopropyl-phenylethynyl]-phenyl}-acetate(Compound 100, General Formula 2)

Using General Procedure F;1-(1-ethoxycyclopropyl)-4-ethynyl-2-isopropylbenzene (Intermediate 103,120.0 mg, 0.52 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 150.0mg, 0.52 mmol) in triethylamine (8 mL) was treated with copper(I)iodide(32.0 mg, 0.17 mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)palladium(II) (121 mg, 0.17 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-5% EtOAc—hexanes) afforded 140.0mg (71%) of the title compound as a pale-yellow oil.

¹H NMR (CDCl₃) δ: 7.53 (3H, m), 7.31-7.23 (4H, m), 3.86 (1H, septet,J=6.7 Hz), 3.73 (3H, s), 3.67 (2H, s), 3.33 (2H, q, J=7.0 Hz), 1.30 (6H,d, J=6.7 Hz), 1.15 (2H, m), 1.08 (3H, t, J=7.0 Hz), 0.90 (2H, m).

4-[4-(1-Ethoxycyclopropyl)-3-isopropyl-phenylethynyl]-benzoic acid(Compound 101, General Formula 2)

Using General Procedure I; A solution of ethyl4-[4-(1-ethoxycyclopropyl)-3-isopropyl-phenylethynyl]-benzoate (Compound99, 28.0 mg, 0.07 mmol) in ethanol (2 mL) and tetrahydrofuran (2 mL) wastreated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution)and stirred overnight at room temperature. Work-up afforded 24 mg (92%)the title compound as a pale-yellow solid.

¹H NMR (d₆-acetone) δ: 8.06 (2H, d, J=8.2 Hz), 7.66 (2H, d, J=8.2 Hz),7.58 (1H, s), 7.33 (2H, m), 3.87 (1H, m), 2.27 (2H, q, J=7.0 Hz), 1.26(6H, d, J=6.7 Hz), 1.09 (2H, m), 0.99 (3H, t, J=7.0 Hz), 0.88 (2H, m).

{4-[4-(1-Ethoxycyclopropyl)-3-isopropyl-phenylethynyl]-phenyl}-aceticacid (Compound 102, General Formula 2)

Using General Procedure I; a solution ofmethyl{4-[4-(1-ethoxycyclopropyl)-3-isopropyl-phenylethynyl]-phenyl}-acetate(Compound 100, 130.0 mg, 0.35 mmol) in ethanol (5 mL) andtetrahydrofuran (5 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0mL of a 1N aqueous solution) and stirred at 50° C. for 4 h. Work-up andisolation by HPLC (Partisil 10-pac, 10% H₂O/CH₃CN) afforded 88.0 mg(70%) of the title compound.

¹H NMR (CDCl₃) δ: 7.50 (3H, m), 7.28-7.19 (4H, m), 3.82 (1H, m), 3.65(2H, s), 3.29 (2H, q, J=7.0 Hz), 1.25 (6H, d, J=6.7 Hz), 1.14 (2H, m),1.04 (3H, t, J=7.0 Hz), 0.86 (2H, m).

4-Bromo-3-tert-butylphenol (Intermediate 104)

To a mixture of 3-tert-butyl-methoxy benzene (1.00 g, 6.09 mmols) inCCl₄ (20 mL), molecular sieves, and silica gel was addedN-bromosuccinimide (1.19 g, 6.70 mmols). This mixture was stirred at 55°C. for 48 h. The resulting mixture was cooled to room temperature,filtered to remove the solids, and the filtrate diluted with EtOAc. Thissolution was washed with H₂O, 10% aqueous HCl, H₂O, saturated aqueousNaHCO₃ and saturated aqueous NaCl before being dried (MgSO₄) andconcentrated under reduced pressure. Column chromatography (2.5%EtOAc—hexanes) afforded 1.15 g (78%) of a 3 to 1 mixture of1-bromo-2-tert-butyl methoxy benzene and 1-bromo-2-methoxy-4-tert-butylbenzene as a colorless oil.

A solution of the isomeric methoxy compounds in 10 mL of CH₂Cl₂ wascooled to 0° C. and treated with a solution (18.5 mL) of BBr₃ in CH₂Cl₂(4.63 g, 18.5 mmols). After 10 minutes the solution was warmed to roomtemperature, stirred for 1 h, and then quenched with H₂O. The mixturewas extracted with EtOAc and the combined organic layers washed withsaturated aqueous NaCl, dried (MgSO₄), and concentrated under reducedpressure. The title compound was isolated, 1.17 g (59%), by columnchromatography (2.5-5% EtOAc—hexanes).

¹H NMR (CDCl₃) δ: 7.39 (1H, d, J=8.5 Hz), 6.96 (1H, d, J=2.9 Hz), 6.54(1H, dd, J=2.9, 8.5 Hz), 1.46 (9H, s).

(4-Bromo-3-tert-butyl-phenoxy)-triisopropyl-silane (Intermediate 105)

To a solution of 4-bromo-3-tert-butylphenol (Intermediate 104, 1.17 g,5.10 mmols) and imidazole (520.0 mg, 7.65 mmols) in 10 mL DMF was addedchloro-triisopropylsilane (1.18 g, 6.10 mmols). After stirring overnightat room temperature the solution was diluted with H₂O and extracted withEtOAc. The combined organic layers were washed with H₂O and saturatedaqueous NaCl before being dried (MgSO₄) and concentrated under reducedpressure. The title compound, 1.80 g (92%), was isolated by columnchromatography (0-1.5% EtOAc—hexanes) as a colorless oil.

¹H NMR (CDCl₃) δ: 7.38 (1H, d, J=8.0 Hz), 6.97 (1H, d, J=2.9 Hz), 6.56(1H, dd, J=2.9, 8.5 Hz), 1.47 (9H, s), 1.29-1.24 (3H, m), 1.09 (18H, d,J=6.7 Hz).

Ethyl 2-tert-butyl-4-triisopropylsilanyloxy-benzoate (Intermediate 106)

To a solution of (4-bromo-3-tert-butyl-phenoxy)-triisopropyi-silane(Intermediate 105, 1.00 g, 2.60 mmols) in 15 mL Et₂O cooled to −78° C.was added 3.6 mL of tert-butyllithium, 1.7 M in pentane (395.0 mg, 6.2mmols). After stirring for 30 minutes ethyl chloroformate (607.6 mg, 5.6mmols) was added. The resulting solution was warmed to room temperatureand quenched by the addition of saturated aqueous NH₄Cl. The mixture wasextracted with EtOAc and the combined organic layers dried (MgSO₄)concentrated under reduced pressure The residue was chromatographed(2-5% EtOAc—hexanes) to give 1.23 g (88%) of the title compound as acolorless oil.

¹H NMR (CDCl₃) δ: 7.24 (1H, d, J=8.2 Hz), 6.97 (1H, d, J=2.6 Hz), 6.69(1H, dd, J=2.6, 8.2 Hz), 4.33 (2H, q, J=7.1 Hz), 1.39 (9H, s), 1.37 (3H,t, J=7.1 Hz), 1.29-1.21 (3H, m), 1.10 (18H, d, J=6.7 Hz).

[4-(1-Ethoxyvinyl)-3-tert-butyl-phenoxy]-triisopropyl-silane(Intermediate 107)

Using General Procedure 1; ethyl2-tert-butyl-4-triisopropylsilanyloxy-benzoate (Intermediate 106, 1.30g, 3.44 mmols) and 7.2 mL of Tebbe's Reagent (1.03 g, 3.61 mmols) werereacted. The reaction required 7 days at room temperature to go tocompletion. The standard work-up afforded 1.29 g (78%) of the titlecompound after column chromatography (1-2% EtOAc—hexanes).

¹H NMR (CDCl₃) δ: 7.05 (1H, d, J=8.2 Hz), 6.94 (1H, d, J=2.6 Hz), 6.63(1H, dd, J=2.6, 8.2 Hz), 4.20 (1H, d, J=1.7 Hz), 4.08 (1H, d, J=1.7 Hz),3.83 (2H, q, J=7.1 Hz), 1.37 (9H, s), 1.36 (3H, t, J=7.1 Hz), 1.27-1.20(3H, m), 1.10 (18H, d, J=6.7 Hz).

[4-(1-Ethoxycyclopropyl)-3-tert-butyl-phenoxy]-triisopropyl-silane(Intermediate 108)

Using General Procedure 2;[4-(1-ethoxyvinyl)-3-tert-butyl-phenoxy]-triisopropyl-silane(Intermediate 107, 320.0 mg, 0.85 mmols), Et₂Zn (325.0 mg, 2.63 mmols),and CH₂I₂ (704.0 mg, 2.63 mmols) in 5.0 mL Et₂O afforded 257.0 mg (66%)of the title compound as a colorless oil after chromatography (1-2.5%EtOAc—hexanes).

¹H NMR (CDCl₃) δ: 7.24 (1H, d, J=8.5 Hz), 7.06 (1H, d, J=2.6 Hz), 6.60(1H, dd, J=2.6, 8.5 Hz), 3.24 (2H, q, J=7.1 Hz), 1.50 (9H, s), 1.29-1.21(3H, m), 1.11 (18H, d, J=6.7 Hz), 1.04 (3H, t, J=7.1 Hz).

4-(1-Ethoxycyclopropyl)-3-tert-butyl-phenol (Intermediate 109)

To a solution of[4-(1-ethoxycyclopropyl)-3-tert-butyl-phenoxy]-triisopropyl-silane(Intermediate 108, 600.0 mg, 1.54 mmol) in 3 mL THF at 0° C. was addedtetrabutylammonium fluoride (802.8.0 mg, 3.07 mmols; 3.1 mL of a 1 Msolution in THF). The solution was stirred at 0° C. for 30 minutes andthen quenched by the addition of H₂O. The mixture was extracted withEtOAc and the combined organic layers were washed with H₂O and saturatedaqueous NaCl before being dried (MgSO₄) and concentrated under reducedpressure. The title compound (400 mg, 88%) was isolated from the residueby column chromatography (4-10% EtOAc—hexanes) as a colorless solid.

¹H NMR (CDCl₃) δ: 7.29 (1H, d, J=8.2 Hz), 7.01 (1H, d, J=2.6 Hz), 6.57(1H, dd, J=2.6, 8.2 Hz), 3.29 (2H, q, J=7.1 Hz), 1.59 (9H, s), 1.08-1.04(7H, m).

4-(1-Ethoxycyclopropyl)-3-tert-butyl-phenyl1,1,1-trifluoromethansulfonate (Intermediate 110)

A solution of 4-(1-ethoxycyclopropyl)-3-tert-butyl-phenol (Intermediate109, 400.0 mg, 1.71 mmol) in 10 mL of CH₂Cl₂ was cooled to 0° C. and toit was added 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine(705.0 mg, 1.79 mmol) and triethylamine (522.0 mg, 5.1 mmols). Theresulting solution was warmed to room temperature and stirred overnight.The reaction was quenched by the addition of H₂O and the mixtureextracted with EtOAc and the combined organic layers were washed with10% aqueous HCl, saturated aqueous NaHCO₃, H₂O, and saturated aqueousNaCl. The solution was dried (MgSO₄) and concentrated under reducedpressure. The title compound was isolated by column chromatography (2-4%EtOAc—hexanes) as a colorless oil, 542.0 mg (87%).

¹H NMR (CDCl₃) δ: 7.48 (1H, d, J=8.5 Hz), 7.39 (1H, d, J=2.6 Hz), 7.01(1H, dd, J=2.6, 8.5 Hz), 3.26 (2H, q, J=7.1 hz), 1.52 (9H, s), 1.12 (2H,bs), 1.08-1.04 (5H, m).

[4-(1-Ethoxycyclopropyl)-3-tert-butyl-phenylethynyl]-trimethylsilane(Intermediate 111)

Using General Procedure D; 4-(1-ethoxycyclopropyl)-3-tert-butyl-phenyl1,1,1-trifluoromethansulfonate (Intermediate 110, 260.0 mg, 0.71 mmol)in triethylamine (4 mL) and DMF (6 mL) was sparged with argon for 5minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then addedfollowed by dichlorobis-(triphenylphosphine)palladium(II) (40.0 mg, 0.06mmol). The resulting reaction mixture was heated to 95° C. for 18 hours.The title compound, 215.0 mg (96%), was isolated by chromatography (0-2%EtOAc—hexanes) as an orange oil.

¹H NMR (CDCl₃) δ: 7.63 (1H, d, J=1.7 Hz), 7.32 (1H, d, J=7.9 Hz), 7.19(1H, dd, J=1.7, 7.9 Hz), 3.24 (2H, q, J=7.1 Hz), 1.51 (9H, s), 1.10 (2H,bs), 1.06-1.01 (5H, m), 0.25 (9H, s).

1-(1-Ethoxycyclopropyl)-4-ethynyl-2-tert-butylbenzene (Intermediate 112)

Using General Procedure E;[4-(1-ethoxycyclopropyl)-3-tert-butyl-phenylethynyl]-trimethylsilane(Intermediate 111, 215.0 mg, 0.69 mmol) in methanol (10 mL) was treatedwith potassium carbonate (80.0 mg, 0.58 mmol) and stirred overnight atambient temperature. The crude alkyne, 169 mg, was used directly in thenext reaction.

¹H NMR (CDCl₃) δ: 7.68 (1H, d, J=1.8 Hz), 7.36 (1H, d, J=7.9 Hz), 7.23(1H, dd, J=1.8, 7.9 Hz), 3.26 (2H, q, J=7.1 Hz), 3.06 (1H, s), 1.51 (9H,s), 1.11 (2H, bs), 1.07-1.02 (5H, m).

Ethyl 4-[4-(1-ethoxycyclopropyl)-3-tert-butyl-phenylethynyl]-benzoate(Compound 103, General Formula 2)

Using General Procedure F;1-(1-ethoxycyclopropyl)-4-ethynyl-2-tert-butylbenzene (Intermediate 112,70.0 mg, 0.30 mmol) and ethyl-4-iodo benzoate (Reagent A, 85.0 mg, 0.30mmol) in triethylamine (5 mL) was treated with copper(I)iodide (19.0 mg,0.01 mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)-palladium(II) (70 mg, 0.01 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (1-2% EtOAc—hexanes) afforded 70.0 mg(73%) of the title compound.

¹H NMR (CDCl₃) δ: 8.02 (2H, d, J=8.8 Hz), 7.72 (1H, d, J=1.7 Hz), 7.59(2H, d, J=8.8 Hz), 7.40 (1H, d, J=7.9 Hz), 7.28 (1H, dd, J=1.7, 7.9 Hz),4.39 (2H, q, J=7.1 Hz), 3.28 (2H, q, J=7.1 Hz), 1.55 (9H, s), 1.40 (3H,t, J=7.1 Hz), 1.12 (2H, bs), 1.08-1.04 (5H, m).

Methyl{4-[4-(1-ethoxycyclopropyl)-3-tert-butyl-phenylethynyl]-phenyl}-acetate(Compound 104, General Formula 2)

Using General Procedure F;1-(1-ethoxycyclopropyl)-4-ethynyl-2-tert-butylbenzene (Intermediate 112,95.0 mg, 0.39 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 108.0mg, 0.39 mmol) in triethylamine (8 mL) was treated with copper(I)iodide(25.0 mg, 0.13 mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)palladium(II) (91 mg, 0.13 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-5% EtOAc—hexanes) afforded 100.0mg (72%) of the title compound.

¹H NMR (CDCl₃) δ: 7.70 (1H, d, J=1.5 Hz), 7.50 (2H, d, J=7.9 Hz), 7.38(1H, d, J=7.9 Hz), 7.27 (3H, m), 3.70 (3H, s), 3.64 (2H, s), 3.28 (2H,q, J=7.1 Hz), 1.54 (9H, s), 1.12 (2H, bs), 1.08-1.03 (5H, m).

4-[4-(1-Ethoxycyclopropyl)-3-tert-butyl-phenylethynyl]-benzoic acid(Compound 105, General Formula 2)

Using General Procedure I; a solution of ethyl4-[4-(1-ethoxycyclopropyl)-3-tert-butyl-phenylethynyl]-benzoate(Compound 103, 70.0 mg, 0.18 mmol) in ethanol (3 mL) and tetrahydrofuran(3 mL) was treated with NaOH (240.0 mg, 6.0 mmols, 3.0 mL of a 2Naqueous solution) and stirred overnight at room temperature. Work-upafforded 40 mg (62%) the title compound as a pale-yellow solid.

¹H NMR (d₆-acetone) δ: 8.06 (2H, d, J=8.7 Hz), 7.76 (1H, d, J=1.8 Hz),7.67 (2H, d, J=8.7 Hz), 7.50 (1H, d, J=7.9 Hz), 7.33 (1H, dd, J=1.8, 7.9Hz), 3.28 (2H, q, J=7.3 Hz), 1.54 (9H, s), 1.13 (2H, bs), 1.10 (2H, m),1.02 (3H, t, J=7.3 Hz).

{4-[4-(1-Ethoxycyclopropyl)-3-tert-butyl-phenylethynyl]-phenyl}-aceticacid (Compound 106, General Formula 2)

Using General Procedure I; a solution ofmethyl{4-[4-(1-ethoxycyclopropyl)-3-tert-butyl-phenylethynyl]-phenyl}-acetate(Compound 104, 100.0 mg, 0.26 mmol) in ethanol (4 mL) andtetrahydrofuran (4 mL) was treated with NaOH (240.0 mg, 6.0 mmols, 3.0mL of a 2N aqueous solution) and stirred at 50° C. for 4 h. Work-up andisolation by HPLC (Partisil 10-pac, 10% H₂O/CH₃CN) afforded 70.0 mg(73%) of the title compound.

¹H NMR (CDCl₃) δ: 7.73 (1H, d, J=1.3 Hz), 7.53 (2H, d, J=7.9 Hz), 7.41(1H, d, J=7.9 Hz), 7.28 (3H, m), 3.69 (2H, s), 3.31 (2H, q, J=7.1 Hz),1.56 (9H, s), 1.15 (2H, bs), 1.11-1.05 (5H, m).

1-(4-Bromophenyl)-cyclopropanecarbonitrile (Intermediate 113)

To a 50% aqueous NaOH solution (40.0 g, wt/wt) was added benzyltriethylammonium chloride (1.0 g, 4.4 mmols), 4-bromobenzonitrile (19.6g, 0.10 mol), and 1,2-dibromoethane (56.4 g, 0.30 mol). The mixture wasstirred overnight at room temperature and then diluted with 100 mL ofH₂O. This mixture was extracted with EtOAc and the combined extractswere washed with saturated aqueous NaHS₂O₃, H₂O, and saturated aqueousNaCl before being dried (MgSO₄) and concentrated under reduced pressure.Bulb-to-bulb distillation afforded 18.8 g (85%) of the title compound asa colorless solid.

¹H NMR (CDCl₃) δ: 7.48 (2H, d, J=8.6 Hz), 7.17 (2H, d, J=8.6 Hz), 1.75(2H, dd, J=5.2, 7.6 Hz), 1.39 (2H, dd, J=5.2, 7.6 Hz).

1-(4-Bromophenyl)-cyclopropanecarboxylic acid (Intermediate 114)

To a solution of KOH (6.06 g, 0.11 mol) in 10 mL of H₂O was added 40 mLof ethylene glycol and 1-(4-bromophenyl)-cyclopropanecarbonitrile(Intermediate 113, 10.0 g, 0.45 mol). This solution was heated to135-140° C. for 4 h, cooled to room temperature, and then poured into amixture of 100 mL ice and 10% aqueous HCl. The resulting mixture wasallowed to stand overnight at 5° C., the solid was collected byfiltration and washed with H₂O. The colorless solid was dried underreduced pressure to give 10.6 g (97%) of the title compound.

¹H NMR (CDCl₃) δ: 7.43 (2H, d, J=8.5 Hz), 7.21 (2H, d, J=8.5 Hz), 1.68(2H, dd, J=4.0, 7.1 Hz), 1.24 (2H, dd, J=4.0, 7.1 Hz).

Tert-butyl [1-(4-bromophenyl)-cyclopropyl]-carbamate (Intermediate 115)

A solution of 1-(4-bromophenyl)-cyclopropanecarboxylic acid(Intermediate 114, 2.32 g, 9.62 mmols), diphenylphosphoryl azide (2.65g, 9.62 mmols), triethylamine (973.0 mg, 9.62 mmols) in 40 mL tert-BuOH(distilled from Na°) was heated to reflux for 17 h. The solution wasconcentrated under reduced pressure and the residue dissolved in EtOAcand washed with 5% aqueous HCl, H₂O, saturated aqueous NaHCO₃, andsaturated aqueous NaCl before being dried over MgSO₄. Concentration ofthe dry solution under reduced pressure and column chromatography (5-10%EtOAc—hexanes) afforded 2.01 g (67%) of the title compound as acolorless solid.

¹H NMR (CDCl₃) δ: 7.39 (2H, d, J=8.3 Hz), 7.08 (2H, d, J=8.3 Hz), 5.35(1H, bs), 1.43 (9H, s), 1.26 (2H, m), 1.17 (2H, m).

1-(4-Bromophenyl)-cyclopropylamine (Intermediate 116)

To a solution of tert-butyl [1-(4-bromophenyl)-cyclopropyl]-carbamate(Intermediate 115, 1.08 g, 3.40 mmols) in 20 mL MeOH and 20 mL THF wasadded 20 mL of 3M aqueous HCl. The solution was warmed to 35° C. for 3hours and then stirred for 17 h at 25° C. The reaction was quenched byadjusting the pH of the solution to 12 with 3M aqueous NaOH. The mixturewas extracted with Et₂O and the combined organic layers were washed withH₂O and saturated aqueous NaCl before being dried (MgSO₄) andconcentrated under reduced pressure. The title compound 613 mg (85%) wasused without further purification.

¹H NMR (CDCl₃) δ: 7.43 (2H, d, J=8.3 Hz), 7.17 (2H, d, J=8.3 Hz), 1.89(2H, bs), 1.07 (2H, m), 0.95 (2H, m).

N-[1-(4-bromophenyl)-cyclopropyl]-propionamide (Intermediate 117)

To a solution of 1-(4-bromophenyl)-cyclopropylamine (Intermediate 116,84 mg, 0.4 mmol) in 4 mL CH₂Cl₂ at room temperature was added propionylchloride (43.0 mg, 0.47 mmol) and pyridine (56.0 mg, 0.71 mmol). Afterstirring 17 hours at room temperature the reaction was quenched by theaddition of H₂O and extracted with EtOAc. The combined extracts werewashed with 10% aqueous HCl, saturated aqueous NaHCO₃, and saturatedaqueous NaCl before being dried (MgSO₄) and concentrated under reducedpressure. The title compound 85.0 mg (67%), was isolated by columnchromatography (20-50% EtOAc—hexanes) as a colorless solid.

¹H NMR (CDCl₃) δ: 7.48 (2H, d, J=8.5 Hz), 7.09 (2H, d, J=8.5 Hz), 6.40(1H, s), 2.19 (2H, q, J=7.2 Hz), 1.18-1.24 (4H, m), 1.12 (3H, t, J=7.2Hz).

[1-(4-Bromophenyl)-cyclopropyl]-propylamine (Intermediate 118)

To a solution of N-[1-(4-bromophenyl)-cyclopropyl]-propionamide(Intermediate 117, 85.0 mg, 0.32 mmol) in THF (5 mL) at 0° C. was addedBH₃-Me₂S (48.0 mg, 0.63 mmol; 0.31 mL of a 2M solution in THF). Thesolution was heated to 55° C. for 17 hours, cooled to room temperature,saturated aqueous NaHCO₃ was added and the resulting mixture was stirredfor 2 hours. This mixture was extracted with EtOAc and the combinedorganic layers were washed with H₂O and saturated aqueous NaCl beforebeing dried (MgSO₄) and concentrated under reduced pressure. The titlecompound was isolated by column chromatography (10-30% EtOAc—hexanes).

¹H NMR (CDCl₃) δ: 7.42 (2H, d, J=8.5 Hz), 7.19 (2H, d, J=8.5 Hz), 2.46(2H, t, J=7.3 Hz), 1.40 (2H, m), 0.98 (2H, m), 0.86 (5H, m).

Propyl-[1-(4-trimethylsilanylethynyl-phenyl)-cyclopropyl] -amine(Intermediate 119)

Using General Procedure D; [1-(4-bromophenyl)-cyclopropyl]-propylamine(Intermediate 118, 100.0 mg, 0.39 mmol) in triethylamine (8 mL) wastreated with copper(I)iodide (13.0 mg, 0.06 mmol) and then sparged withargon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 7.1 mmols) wasthen added followed by dichlorobis(triphenylphosphine)palladium(II)(48.0 mg, 0.06 mmol). The resulting reaction mixture was heated to 70°C. for 5 days. The title compound (80.0 mg, 75%) was isolated bychromatography (0-10% EtOAc—hexanes) as an orange oil.

¹H NMR (CDCl₃) δ: 7.41 (2H, d, J=8.5 Hz), 7.21 (2H, d, J=8.5 Hz), 2.45(2H, t, J=7.3 Hz), 1.39 (2H, m), 0.98 (2H, m), 0.87 (2H, m), 0.84 (3H,t, J=7.3 Hz), 0.24 (9H, s).

[1-(4-Ethynylphenyl)-cyclopropyl]-propylamine (Intermediate 120)

Using General Procedure E;propyl-[1-(4-trimethylsilanylethynyl-phenyl)-cyclopropyl]-amine(Intermediate 119, 80.0 mg, 30.0 mmols) in methanol (8 mL) was treatedwith potassium carbonate (80.0 mg, 0.59 mmol) and stirred overnight atambient temperature. The crude alkyne (58 mg, 100%) was used directly inthe next reaction.

¹H NMR (CDCl₃) δ: 7.44 (2H, d, J=8.5 Hz), 7.24 (2H, d, J=8.5 Hz), 3.05(1H, s), 2.46 (2H, t, J=7.3 Hz), 1.41 (2H, m), 1.00 (2H, m), 0.90 (2H,m), 0.86 (3H, t, J=7.3 Hz).

Ethyl 4-[4-(1-propylamino-cyclopropyl)-phenylethynyl]-benzoate (Compound107, General Formula 2)

Using General Procedure F; [1-(4-ethynylphenyl)-cyclopropyl]-propylamine(Intermediate 120, 38.0 mg, 0.19 mmol) and ethyl-4-iodo benzoate(Reagent A, 58.0 mg, 0.21 mmol) in triethyl amine (6 mL) was treatedwith copper(I)iodide (8.0 mg, 0.04 mmol) and sparged with argon for 5minutes. Dichlorobis(triphenylphosphine)palladium(II) (27 mg, 0.04 mmol)was added and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (5-15% EtOAc—hexanes) afforded 40.0mg (61%) of the title compound as an orange oil.

¹H NMR (CDCl₃) δ: 8.01 (2H, d, J=8.5 Hz), 7.57 (2H, d, J=8.5 Hz), 7.49(2H, d, J=8.5 Hz), 7.28 (2H, d, J=8.5 Hz), 4.39 (2H, q, J=7.1 Hz), 2.49(2H, t, J=7.3 Hz), 1.46 (2H, m), 1.41 (3H, t, J=7.1 Hz), 1.01 (2H, m),0.89 (2H, m), 0.87 (3H, t, J=7.3 Hz).

4-[4-(1-Propylamino-cyclopropyl)-phenylethynyl]-benzoic acid (Compound108, General Formula 2)

Using General Procedure I; a solution of ethyl4-[4-(1-propylamino-cyclopropyl)-phenylethynyl]-benzoate (Compound 107,40.0 mg, 0.12 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) wastreated with NaOH (160.0 mg, 4.0 mmols, 2.0 mL of a 2N aqueous solution)and stirred overnight at room temperature. Work-up afforded 25.0 mg(69%) of the title compound as a solid.

¹H NMR (d₆-DMSO) δ: 7.97 (2H, d, J=8.5 Hz), 7.65 (2H, d, J=8.5 Hz), 7.50(2H, d, J=8.5 Hz), 7.36 (2H, d, J=8.5 Hz), 2.39 (2H, t, J=7.3 Hz), 1.37(2H, m), 1.00 (2H, m), 0.93 (2H, m), 0.84 (3H, t, J=7.3 Hz).

[1-(4-Bromophenyl)-cyclopropyl]-dipropylamine (Intermediate 121)

To a solution of 1-(4-bromophenyl)-cyclopropylamine (Intermediate 116)in CH₃CN/HOAc (5 mL, 9:1, v/v) and THF 3 mL at 0° C. was addedpropionaldehyde (277.0 mg, 4.95 mmols) and NaCNBH₃ (153.0 mg, 2.47mmols). The reaction was warmed to room temperature and after 5 hoursquenched with H₂O. The pH of the solution was adjusted to 8-9 usingaqueous NaOH and extracted with EtOAc. The combined extracts were washedwith H₂O and saturated aqueous NaCl, dried (MgSO₄) and concentratedunder reduced pressure. The title compound, 190.0 mg (56%), was isolatedby column chromatography (2-5% EtOAc—hexanes).

¹H NMR (CDCl₃) δ: 7.42 (2H, d, J=8.3 Hz), 7.18 (2H, d, J=8.3 Hz), 2.39(4H, t, J=7.3 Hz), 1.62-1.40 (4H, m), 0.96 (2H, m), 0.86 (6H, t, J=7.3Hz), 0.80 (2H, m).

Dipropyl-[1-(4-trimethylsilanylethynyl-phenyl)-cyclopropyl]-amine(Intermediate 122)

Using General Procedure D; [1-(4-bromophenyl)-cyclopropyl]-dipropylamine(Intermediate 121, 150.0 mg, 0.50 mmol) in triethylamine (5 mL) wastreated with copper(I)iodide (10.0 mg, 0.05 mmol) and then sparged withargon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 7.1 mmols) wasthen added followed by dichlorobis(triphenylphosphine)palladium(II)(35.0 mg, 0.05 mmol). The resulting reaction mixture was heated to 70°C. for 5d. The title compound was isolated by chromatography (0-3%EtOAc—hexanes).

¹H NMR (CDCl₃) δ: 7.35 (2H, d, J=8.3 Hz), 7.24 (2H, d, J=8.3 Hz), 2.39(4H, t, J=7.3 Hz), 1.55-1.42 (4H, m), 0.96 (2H, m), 0.88-0.79 (8H, m),0.25 (9H, s).

[1-(4-Ethynylphenyl)-cyclopropyl]-dipropylamine (Intermediate 123)

Using General Procedure E;dipropyl-[1-(4-trimethylsilanylethynyl-phenyl)-cyclopropyl]-amine(Intermediate 122, 45.0 mg, 0.14 mmols) in methanol (5 mL) was treatedwith potassium carbonate (50.0 mg, 0.37 mmol) and stirred overnight atambient temperature. The crude alkyne (34 mg, 100%) was used directly inthe next reaction.

¹H NMR (CDCl₃) δ: 7.42 (2H, d, J=8.3 Hz), 7.28 (2H, d, J=8.3 Hz),2.40(4H, t, J=7.3 Hz), 1.53-1.40 (4H, m), 0.96 (2H, m), 0.90-0.79 (8H,m).

Ethyl 4-[4-(1-dipropylamino-cyclopropyl)-phenylethynyl]-benzoate(Compound 109, General Formula 2)

Using General Procedure F;[1-(4-ethynylphenyl)-cyclopropyl]-dipropylamine (Intermediate 123, 34.0mg, 0.16 mmol) and ethyl-4-iodo benzoate (Reagent A, 59.0 mg, 0.21 mmol)in triethyl amine (6 mL) was treated with copper(I)iodide (13.0 mg, 0.07mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)palladium(II) (49 mg, 0.07 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-4% EtOAc—hexanes) afforded thetitle compound as a yellow oil.

¹H NMR (CDCl₃) δ: 8.03 (2H, d, J=8.2 Hz), 7.58 (2H, d, J=8.2 Hz), 7.49(2H, d, J=8.2 Hz), 7.30 (2H, d, J=8.2 Hz), 4.39 (2H, q, J=7.1 Hz), 2.43(4H, t, J=7.3 Hz), 1.52-1.42 (4H, m), 1.41 (3H, t, J=7.1 Hz), 0.99 (2H,m), 0.88-0.83 (8H, m).

4-[4-(1-Dipropylamino-cyclopropyl)-phenylethynyl]-benzoic acid (Compound110, General Formula 2)

Using General Procedure I; a solution of ethyl4-[4-(1-dipropylamino-cyclopropyl)-phenylethynyl]-benzoate (Compound109, 51.0 mg, 0.13 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL)was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueoussolution) and stirred overnight at room temperature. Work-up afforded32.0 mg (70%) of the title compound as a colorless solid.

¹H NMR (d₆-DMSO) δ: 7.98 (2H, d, J=8.3 Hz), 7.67 (6H, m), 3.05-2.89 (4H,m), 1.98 (2H, m), 1.72 (4H, m), 1.23 (2H, m), 0.88 (6H, t, J=7.3 Hz).

Benzyl-[1-(4-bromophenyl)-cyclopropyl]-amine (Intermediate 124) andDibenzyl-[1-(4-bromophenyl)-cyclopropyl]-amine (Intermediate 125)

A solution of 1-(4-bromophenyl)-cyclopropylamine (Intermediate 116,244.0 mg, 1.15 mmols) and benzyl bromide (255.0 mg, 1.50 mmols) in 4 mLDMF was stirred at 85° C. for 6 hours, cooled to room temperature andstirred overnight. The solution was diluted with H₂O and the pH adjustedto 8-9 with aqueous NaOH. The solution was extracted with EtOAc and thecombined organic layers were washed with H₂O and saturated aqueous NaCl,dried (MgSO₄) and concentrated under reduced pressure. Columnchromatography (5-10% EtOAc—Hexanes) afforded 110 mg (32%) of theN-benzyl amine.

¹H NMR (CDCl₃) δ: 7.48 (2H, d, J=8.4 Hz), 7.30-7.23 (7H, m), 3.68 (2H,s), 1.07 (2H, m), 0.93 (2H, m); and 100 mg (22%) of the N,N-dibenzylamine, ¹H NMR (CDCl₃) δ: 7.55 (2H, d, J=8.3 Hz), 7.40-7.19 (12H, m),3.61 (4H, s), 0.87 (2H, m), 0.71 (2H, m).

Benzyl-[1-(4-trimethylsilanylethynyl-phenyl)-cyclopropyl]-amine(Intermediate 126)

Using General Procedure D; benzyl-[1-(4-bromophenyl)-cyclopropyl]-amine(Intermediate 124, 110.0 mg, 0.36 mmol) in triethylamine (8 mL) wastreated with copper(I)iodide (10.0 mg, 0.05 mmol) and then sparged withargon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 7.1 mmols) wasthen added followed by dichlorobis(triphenylphosphine)palladium(II)(38.0 mg, 0.05 mmol). The resulting reaction mixture was heated to 70°C. for 5d. The title compound 85 mg (74%) was isolated by chromatography(1-10% EtOAc—hexanes).

¹H NMR (CDCl₃) δ: 7.46 (2H, d, J=8.3 Hz), 7.31-7.22 (7H, m), 3.67 (2H,s), 1.06 (2H, m), 0.94 (2H, m), 0.26 (9H, s).

Benzyl-[1-(4-ethynylphenyl)-cyclopropyl]-amine (Intermediate 127)

Using General Procedure E;benzyl-[1-(4-trimethylsilanylethynyl-phenyl)-cyclopropyl]-amine(Intermediate 126, 85.0 mg, 0.27 mmol) in methanol (5 mL) was treatedwith potassium carbonate (50.0 mg, 0.37 mmol) and stirred overnight atambient temperature. The crude alkyne (65 mg, 100%) was used directly inthe next reaction.

¹H NMR (CDCl₃) δ: 7.49 (2H, d, J=7.9 Hz), 7.32 (2H, d, J=7.9 Hz), 7.23(5H, m), 3.68 (2H, s), 3.08 (1H, s), 1.07 (2H, m), 0.95 (2H, m).

Ethyl 4-[4-(1-benzylamino-cyclopropyl)-phenylethynyl]-benzoate (Compound111, General Formula 2)

Using General Procedure F;benzyl-[1-(4-ethynylphenyl)-cyclopropyl]-amine (Intermediate 127, 65.0mg, 0.27 mmol) and ethyl-4-iodo benzoate (Reagent A, 68.0 mg, 0.27 mmol)in triethyl amine (8 mL) was treated with copper(I)iodide (16.0 mg, 0.08mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (58 mg, 0.08 mmol) was added and thereaction mixture was stirred overnight at room temperature. Columnchromatography (2-5% EtOAc—hexanes) afforded 90 mg (90%) of the titlecompound as an orange solid.

¹H NMR (CDCl₃) δ: 8.05 (2H, d, J=8.3 Hz), 7.61 (2H, d, J=8.3 Hz), 7.55(2H, d, J=8.1 Hz), 7.43 (2H, d, J=8.1 Hz), 7.32-7.22 (5H, m), 4.40 (2H,q, J=7.1 Hz), 3.72 (2H, s), 1.42 (2H, t, J=7.1 Hz), 1.01 (2H, m), 0.99(2H, m).

4-[4-(1-Benzylamino-cyclopropyl)-phenylethynyl]-benzoic acid (Compound112, General Formula 2)

Using General Procedure I; a solution of ethyl4-[4-(1-benzylamino-cyclopropyl)-phenylethynyl]-benzoate (Compound 111,75.0 mg, 0.19 mmol) in ethanol (4 mL) and tetrahydrofuran (4 mL) wastreated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution)and stirred overnight at room temperature. Work-up afforded 35.0 mg(50%) of the title compound as a colorless solid.

¹H NMR (CD₃OD) δ: 7.93 (2H, d, J=8.3 Hz), 7.61-7.51 (6H, m), 7.32-7.23(5H, m), 3.98 (2H, s), 1.33(2H, m), 1.19 (2H, m).

Dibenzyl-[1-(4-trimethylsilanylethynyl-phenyl)-cyclopropyl]-amine(Intermediate 128)

Using General Procedure D;dibenzyl-[1-(4-bromophenyl)-cyclopropyl]-amine (Intermediate 125, 45.0mg, 0.11 mmol) in triethylamine (8 mL) was treated with copper(I)iodide(10.0 mg, 0.05 mmol) and then sparged with argon for 5 minutes.Trimethylsilyl acetylene (0.35 g, 3.6 mmols) was then added followed bydichlorobis(triphenylphosphine)palladium(II) (35.0 mg, 0.05 mmol). Theresulting reaction mixture was heated to 70° C. for 5d. The titlecompound 40 mg (88%) was isolated by chromatography (hexanes).

¹H NMR (CDCl₃) δ: 7.52 (2H, d, J=8.3 Hz), 7.36-7.24 (12H, m), 3.60 (4H,s), 0.87 (2H, m), 0.67 (2H, m), 0.29 (9H, s).

Dibenzyl-[1-(4-ethynylphenyl)-cyclopropyl]-amine (Intermediate 129)

Using General Procedure E;dibenzyl-[1-(4-trimethylsilanylethynyl-phenyl)-cyclopropyl]-amine(Intermediate 128, 100.0 mg, 0.26 mmol) in methanol (5 mL) was treatedwith potassium carbonate (60.0 mg, 0.44 mmol) and stirred overnight atambient temperature. The crude alkyne (80 mg, 99%) was used directly inthe next reaction.

¹H NMR (CDCl₃) δ: 7.53 (2H, d, J=7.9 Hz), 7.36 (2H, d, J=7.9 Hz),7.28-7.25 (10H, m), 3.62 (4H, s), 3.11 (1H, s), 0.88 (2H, m), 0.68 (2H,m).

Ethyl 4-[4-(1-dibenzylamino-cyclopropyl)-phenylethynyl]-benzoate(Compound 113, General Formula 2)

Using General Procedure F;dibenzyl-[1-(4-ethynylphenyl)-cyclopropyl]-amine (Intermediate 129, 40.0mg, 0.12 mmol) and ethyl-4-iodo benzoate (Reagent A, 60.0 mg, 0.22 mmol)in triethylamine (5 mL) was treated with copper(I)iodide (8.0 mg, 0.04mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (27 mg, 0.04 mmol) was added and thereaction mixture was stirred overnight at room temperature. Columnchromatography (2-5% EtOAc—hexanes) afforded the title compound as anoil.

¹H NMR (CDCl₃) δ: 8.04 (2H, d, J=8.5 Hz), 7.79 (4H, m), 7.42 (2H, d,J=7.9 Hz), 7.29-7.17 (10H, m), 4.40 (2H, q, J=7.1 Hz), 3.63 (4H, s),1.42 (3H, t, J=7.1 Hz), 0.88 (2H, m), 0.73 (2H, m).

4-[4-(1-Dibenzylamino-cyclopropyl)-phenylethynyl]-benzoic acid (Compound114, Formula 2)

Using General Procedure I; a solution of ethyl4-[4-(1-dibenzylamino-cyclopropyl)-phenylethynyl]-benzoate (Compound113, 48.0 mg, 0.10 mmol) in ethanol (2 mL) and tetrahydrofuran (2 mL)was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueoussolution) and stirred overnight at room temperature. Work-up afforded42.0 mg (93%) of the title compound as a colorless solid.

¹H NMR (d₆-DMSO) δ: 7.98 (2H, d, J=8.2 Hz), 7.67 (2H, d, J=8.2 Hz), 7.64(2H, d, J=7.9 Hz), 7.47 (2H, d, J=7.9 Hz), 7.28-7.20 (10H, m), 3.57 (4H,s), 0.84 (2H, m), 0.69 (2H, m).

Benzyl-[1-(4-bromophenyl)-cyclopropyl]-methylamine (Intermediate 130)

To a solution of benzyl-[1-(4-bromophenyl)-cyclopropyl]-amine(Intermediate 124, 100.0 mg, 0.33 mmol) in 5 mL of acetone was addedK₂CO₃ (91 mg, 0.66 mmol) and iodomethane (2.28 g, 16.1 mmols). Theresulting mixture was stirred at 25° C. for 20 hours, diluted with Et₂O,and washed with H₂O and saturated aqueous NaCl. The solution was dried(MgSO₄) and concentrated under reduced pressure to give 90 mg (86%) ofthe title compound.

¹H NMR (CDCl₃) δ: 7.47 (2H, d, J=8.5 Hz), 7.29-7.18 (7H, m), 3.53 (2H,s), 2.07 (3H, s), 1.07 (2H, m), 0.86 (2H, m).

Benzyl-[1-(4-trimethylsilanylethynyl-phenyl)-cyclopropyl]-methylamine(Intermediate 131)

Using General Procedure D;benzyl-[1-(4-bromophenyl)-cyclopropyl]-methylamine (Intermediate 130,90.0 mg, 0.28 mmol) in triethylamine (8 mL) was treated withcopper(I)iodide (6.0 mg, 0.03 mmol) and then sparged with argon for 5minutes. Trimethylsilyl acetylene (0.70 g, 7.1 mmols) was then addedfollowed by dichlorobis(triphenylphosphine)palladium(II) (20.0 mg, 0.03mmol). The resulting reaction mixture was heated to 70° C. for 5 days.The title compound 80 mg (84%) was isolated by chromatography (0-2%EtOAc—hexanes).

¹H NMR (CDCl₃) δ: 7.46 (2H, d, J=8.2 Hz), 7.32-7.18 (7H, m), 3.52 (2H,s), 2.06 (3H, s), 1.06 (2H, m), 0.87(2H, m), 0.26 (9H, s).

Benzyl-[1-(4-ethynylphenyl)-cyclopropyl]-methylamine (Intermediate 132)

Using General Procedure E;benzyl-[1-(4-trimethylsilanylethynyl-phenyl)-cyclopropyl]-methylamine(Intermediate 131, 80.0 mg, 0.24 mmol) in methanol (5 mL) was treatedwith potassium carbonate (80.0 mg, 0.59 mmol) and stirred overnight atambient temperature. The crude alkyne (60 mg, 99%) was used directly inthe next reaction.

¹H NMR (CDCl₃) δ: 7.49 (2H, d, J=8.2 Hz), 7.33-7.21 (7H, m), 3.55 (2H,s), 3.08 (1H, s), 2.08 (3H, s), 1.07 (2H, m), 0.89 (2H, m).

Ethyl 4-{4-[1-(benzyl-methylamino)-cyclopropyl]-phenylethynyl}-benzoate(Compound 115, General Formula 2)

Using General Procedure F;benzyl-[1-(4-ethynylphenyl)-cyclopropyl]-methylamine (Intermediate 132,70.0 mg, 0.28 mmol) and ethyl-4-iodo benzoate (Reagent A, 77.0 mg, 0.28mmol) in triethylamine (5 mL) was treated with copper(I)iodide (18.0 mg,0.10 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (65 mg, 0.10 mmol) was added and thereaction mixture was stirred overnight at room temperature. Columnchromatography (2-5% EtOAc—hexanes) afforded 86 mg (75%) of the titlecompound as an oil.

¹H NMR (CDCl₃) δ: 8.03 (2H, d, J=8.5 Hz), 7.59 (2H, d, J=8.5 Hz), 7.53(2H, d, J=8.2 Hz), 7.36 (2H, d, J=8.2 Hz), 7.25 (5H, m), 4.39 (2H, q,J=7.1 Hz), 3.57 (2H, s), 2.10 (3H, s), 1.41 (3H, t, J=7.1 Hz), 1.10 (2H,m), 0.92 (2H, m).

4-[4-(1-Benzylmethylamino-cyclopropyl)-phenylethynyl]-benzoic acid(Compound 116, General Formula 2)

Using General Procedure I; a solution of ethyl4-{4-[1-(benzyl-methylamino)-cyclopropyl]-phenylethynyl}-benzoate(Compound 115, 65.0 mg, 0.16 mmol) in ethanol (3 mL) and tetrahydrofuran(3 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueoussolution) and stirred overnight at room temperature. Work-up afforded45.0 mg (75%) of the title compound as a solid.

¹H NMR (d₆-DMSO) δ: 7.96 (2H, d, J=8.3 Hz), 7.66 (2H, d, J=8.3 Hz), 7.58(2H, d, J=8.2 Hz), 7.42 (2H, d, J=8.2 Hz), 7.29-7.18 (5H, m), 3.52 (2H,s), 2.00 (3H, s),1.02 (2H, m), 0.87 (2H, m).

(4-Bromo-2-methyl-phenyl)-mnethanol (Intermediate 133)

A solution of methyl 4-bromo-2-methyl-benzoate (1.05 g, 4.58 mmols) in10 mL of Et₂O was cooled to 0° C. and treated with LiAlH₄ (177.0 mg,4.58 mmols), stirred for 3 hours, and then carefully quenched with H₂O.The mixture was extracted with Et₂O and the combined organic layers werewashed with H₂O and saturated aqueous NaCl, dried (MgSO₄), andconcentrated under reduced pressure. The title compound, 830.0 mg (90%),was isolated by column chromatography (10-30% EtOAc—hexanes) as acolorless oil.

¹H NMR (CDCl₃) δ: 7.30 (2H, m), 7.18 (1H, d, J=8.8 Hz), 4.57 (2H, d,J=5.5 Hz), 2.27 (3H, s), 2.13 (1H, t, J=5.5 Hz).

(4-Bromo-2-methyl-benzyloxy)-trimethylsilane (Intermediate 134)

To a solution of (4-bromo-2-methyl-phenyl)-methanol (Intermediate 133,500.0 mg, 2.48 mmols), in 10 mL THF was added triethylamine (374.0 mg,3.70 mmols) and chlorotrimethylsilane (297.0 mg, 2.70 mmols). Theresulting solution was stirred for 17 hours at 25° C. and then treatedwith H₂O and extracted with Et₂O. The combined organic layers werewashed with H₂O, 10% aqueous HCl, saturated NaHCO₃, and saturated NaClbefore being dried (MgSO₄) and concentrated under reduced pressure. Thetitle compound, 550.0 mg (81%), was isolated by column chromatography(5% EtOAc—hexanes) as a colorless oil.

¹H NMR (CDCl₃) δ: 7.35-7.28 (3H, m), 4.64 (2H, s), 2.29 (3H, s), 0.20(9H, s).

2-Methyl-4-trimethylsilanylethynyl-1-trimethylsilanyloxymethyl-benzene(Intermediate 135)

Using General Procedure D; (4-bromo-2-methyl-benzyloxy)-trimethylsilane(Intermediate 134, 550.0 mg, 2.01 mmol) in triethylamine (8 mL) wastreated with copper(I)iodide (38.0 mg, 0.20 mmol) and then sparged withargon for 5 minutes. Trimethylsilyl acetylene (1.05 g, 10.6 mmols) wasthen added followed by dichlorobis(triphenylphosphine)palladium(II)(142.0 mg, 0.20 mmol). The resulting reaction mixture was heated to 70°C. for 5 days. The title compound (380.0 mg, 65%) was isolated bychromatography (0-2% EtOAc—hexanes) as an orange oil.

¹H NMR (CDCl₃) δ: 7.31 (3H, m), 4.64 (2H, s), 2.24 (3H, s), 0.24 (9H,s), 0.15 (9H, s).

(4-Ethynyl-2-methyl-phenyl)-methanol (Intermediate 136)

Using General Procedure E;2-methyl-4-trimethylsilanylethynyl-1-trimethylsilananyloxymethyl-benzene(Intermediate 135, 380.0 mg, 1.30 mmols) in methanol (10 mL) was treatedwith potassium carbonate (180.0 mg, 1.3 mmol) and stirred overnight atambient temperature. The crude alkyne was purified by columnchromatography (5-20% EtOAc—hexanes) to give 100.0 mg (34%) of the titlecompound.

¹H NMR (CDCl₃) δ: 7.06 (3H, m), 4.42 (2H, d, J=5.2 Hz), 2.81 (1H, s),2.05 (3H, s), 1.59 (1H, t, J=5.2 Hz).

Ethyl 4-(4-hydroxymethyl-3-methyl-phenylethynyl)-benzoate (Compound 117,General Formula 6)

Using General Procedure F; (4-ethynyl-2-methyl-phenyl)-methanol(Intermediate 136, 100.0 mg, 0.44 mmol) and ethyl-4-iodo benzoate(Reagent A, 125.0 mg, 0.45 mmol) in triethyl amine (4 mL) was treatedwith copper(I)iodide (29 mg, 0.15 mmol) and sparged with argon for 5minutes. Dichlorobis(triphenylphosphine)palladium(II) (102 mg, 0.15mmol) was added and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (20-40% EtOAc—hexanes) afforded 130.0mg (99%) of the title compound as an orange solid.

¹H NMR (CDCl₃) δ: 7.98 (2H, d, J=8.2 Hz), 7.56 (2H, d, J=8.2 Hz), 7.36(3H, m), 4.65 (2H, s), 4.36 (2H, q, J=7.1 Hz), 2.40 (1H, s), 2.30 (3H,s), 1.39 (3H, t, J=7.1 Hz).

Ethyl 4-(4-bromomethyl-3-methyl-phenylethynyl)-benzoate (Intermediate137)

A solution of ethyl 4-(4-hydroxymethyl-3-methyl-phenylethynyl)-benzoate(Compound 117, 130.0 mg, 0.44 mmol) and triphenylphosphine (150.0 mg,0.57 mmol) in 5 mL CH₂Cl₂ was cooled to 0° C. and N-bromosuccinimide(101.0 mg, 0.57 mmol) was added in 5 portions over 20 minutes. Thesolution was warmed to 25° C. and stirred for 17 hours. The reaction wasquenched by the addition of dilute aqueous NaHCO₃. The resulting mixturewas extracted with Et₂O and the combined organic layers were washed withH₂O and saturated aqueous NaCl before being dried (Na₂SO₄) andconcentrated under reduced pressure. The title compound, 120.0 mg (76%),was isolated by column chromatography (2-5% EtOAc—hexanes) as acolorless solid.

¹H NMR (CDCl₃) δ: 8.01 (2H, d, J=8.1 Hz), 7.56 (2H, d, J=8.1 Hz), 7.32(3H, m), 4.48 (2H, s), 4.38 (2H, q, J=7.1 Hz), 2.40 (3H, s), 1.39 (3H,t, J=7.1 Hz).

Ethyl 4-(4-imidazol-1-yl-methyl-3-methyl-phenylethynyl)-benzoate(Compound 118, General Formula 6)

A solution of imidazole (30.0 mg, 0.44 mmol) in 2 mL DMF was treatedwith NaH (11.0 mg, 0.44 mmol) and heated to 90° C. After 1 h a solutionof ethyl 4-(4-bromomethyl-3-methyl-phenylethynyl)-benzoate (Intermediate137, 120.0 mg, 0.34 mmol) in 2 mL DMF was added and stirring at 90° C.continued for 1 hour. The solution was cooled to room temperature andconcentrated under reduced pressure. The title compound, 90.0 mg (71%)was isolated by column chromatography (20-100% EtOAc—hexanes) as acolorless solid.

¹H NMR (CDCl₃) δ: 8.02 (2H, d, J=8.5 Hz), 7.57 (2H, d, J=8.5 Hz), 7.51(1H, s), 7.40 (1H, s), 7.36 (1H, dd, J=1.2, 7.9 Hz), 7.10 (1H, s), 6.93(1H, d, J=7.9 Hz), 6.88 (1H, t, J=1.7 Hz), 5.12 (2H, s), 4.38 (2H, q,J=7.1 Hz), 2.27 (3H, s), 1.40 (3H, t, J=7.1 Hz).

4-(4-Imidazol-1-yl-methyl-3-methyl-phenylethynyl)-benzoic acid (Compound119, General Formula 6)

Using General Procedure I; a solution of ethyl4-(4-imidazol-1-ylmethyl-3-methyl-phenylethynyl)-benzoate (Compound 118,82.0 mg, 0.24 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) wastreated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution)and stirred overnight at room temperature. Work-up afforded 51.0 mg(68%) of the title compound as a solid.

¹H NMR (d₆-DMSO) δ: 9.20 (1H, s), 7.97 (2H, d, J=8.2 Hz), 7.73 (2H, m),7.65 (2H, d, J=8.2 Hz), 7.52 (1H, s), 7.46 (1H, d, J=7.9 Hz), 7.13 (1H,d, J=7.9 Hz), 5.50 (2H, s), 2.32 (3H, s).

4-Bromo-1-bromomethyl-2-methyl-benzene (Intermediate 138)

A solution of (4-bromo-2-methyl-phenyl)-methanol (Intermediate 133,319.0 mg, 1.58 mmol) and triphenylphosphine (466.0 mg, 1.74 mmol) in 5mL CH₂Cl₂ was cooled to 0° C. and N-bromosuccinimide (309.0 mg, 1.74mmol) was added in 5 portions over 20 minutes. The solution was warmedto 25° C. and stirred for 17 hours. The reaction was quenched by theaddition of dilute aqueous NaHCO₃. The resulting mixture was extractedwith Et₂O and the combined organic layers were washed with H₂O andsaturated aqueous NaCl before being dried (Na₂SO₄) and concentratedunder reduced pressure. The title compound, 350.0 mg (84%), was isolatedby column chromatography (2-3% EtOAc—hexanes) as a colorless oil.

¹H NMR (CDCl₃) δ: 7.32 (1H, d, J=2.0 Hz), 7.29 (1H, dd, J=2.0, 7.9 Hz),7.15 (1H, d, J=7.9 Hz), 4.43 (2H, s), 2.37 (3H, s).

1-(4-Bromo-2-methyl-benzyl)-1H-imidazole (Intermediate 139)

A solution of imidazole (58.0 mg, 0.86 mmol) in 3 mL DMF was treatedwith NaH (20.0 mg, 0.86 mmol) and heated to 90° C. After 1 h a solutionof 4-bromo-1-bromomethyl-2-methyl-benzene (Intermediate 138, 190.0 mg,0.72 mmol) in 3 mL DMF was added and stirring at 90° C. continued for 1hour. The solution was cooled to room temperature and concentrated underreduced pressure. The title compound, 160.0 mg (88%) was isolated bycolumn chromatography (5% MeOH-EtOAc) as a colorless solid.

¹H NMR (CDCl₃) δ: 7.46 (1H, s), 7.34 (1H, dd, J=1.8 Hz), 7.30 (1H, dd,J=1.8, 8.2 Hz), 7.08 (1H, t,J=1.2 Hz), 6.83 (1H, t, J=1.2 Hz), 6.80 (1H,d, J=8.2 Hz), 5.03 (2H, s), 2.23 (3H, s).

1-(2-Methyl-4-trimethylsilanylethynyl-benzyl)-1H-imidazole (Intermediate140)

Using General Procedure D; 1-(4-bromo-2-methyl-benzyl)-1H-imidazole(Intermediate 139, 160.0 mg, 0.64 mmol) in triethylamine (8 mL) wastreated with copper(I)iodide (12.0 mg, 0.07 mmol) and then sparged withargon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 0.71 mmols) wasthen added followed by dichlorobis(triphenylphosphine)palladium(II)(45.0 mg, 0.07 mmol). The resulting reaction mixture was heated to 70°C. for 5 days. The title compound (140.0 mg, 82%) was isolated bychromatography (5% MeOH-EtOAc) as an orange oil.

¹H NMR (CDCl₃) δ: 7.53 (1H, s), 7.38 (1H, s), 7.34 (1H, d, J=8.0 Hz),7.15 (1H, s), 6.94 (1H, s), 6.91 (1H, d, J=8.0 Hz), 5.14 (2H, s), 2.29(3H, s), 0.31 (9H, s).

1-(4-Ethynyl-2-methyl-benzyl)-1H-imidazole (Intermediate 141)

Using General Procedure E;1-(2-methyl-4-trimethylsilanylethynyl-benzyl)-1H-imidazole (Intermediate140, 140.0 mg, 0.53 mmols) in methanol (5 mL) was treated with potassiumcarbonate (100.0 mg, 0.72 mmol) and stirred overnight at ambienttemperature. The crude alkyne (105 mg, 100%) was used directly in thenext reaction.

¹H NMR (CDCl₃) δ: 7.49 (1H, s), 7.35 (1H, s), 7.31 (1H, dd, J=1.7, 7.9Hz), 7.10 (1H, s), 6.69 (1H, d, J=7.9 Hz), 6.85 (1H, t, J=1.2 Hz), 5.14(2H, s), 3.08 (1H, s), 2.26 (3H, s).

Methyl[4-(4-imidazol-1-yl-methyl-3-methyl-phenylethynyl)-phenyl]-acetate(Compound 120, General Formula 6)

Using General Procedure F; 1-(4-ethynyl-2-methyl-benzyl)-1H-imidazole(Intermediate 141, 101.0 mg, 0.53 mmol) andmethyl-(4-iodophenyl)-acetate (Reagent B, 145.0 mg, 0.53 mmol) intriethylamine (5 mL) was treated with copper(I)iodide (34.0 mg, 0.18mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)palladium(II) (124 mg, 0.18 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (5% MeOH-EtOAc) afforded 45.0 mg(25%) of the title compound as an orange oil.

¹H NMR (CDCl₃) δ: 7.47 (3H, m), 7.35 (3H, m), 7.27 (3H, m), 6.91 (1H, d,J=7.3 Hz), 5.11 (2H, s), 3.70 (3H, s), 3.64 (2H, s), 2.26 (3H, s).

[4-(4-Imidazol-1-yl-methyl-3-methyl-phenylethynyl)-phenyl]-acetic acid(Compound 121, General Formula 6)

Using General Procedure I; a solution of methyl[4-(4-imidazol-1-ylmethyl-3-methyl-phenylethynyl)-phenyl]-acetate(Compound 120, 45.0 mg, 0.13 mmol) in ethanol (2 mL) and tetrahydrofuran(2 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueoussolution) and stirred overnight at room temperature. Work-up afforded30.0 mg (70%) of the title compound as a pale-orange solid.

¹H NMR (d₄-MeOH) δ: 8.97 (1H, s), 7.60 (2H, d J=8.8 Hz), 7.47 (3H, m),7.41 (1H, d, J=7.9 Hz), 7.30 (2H, d, J=7.9 Hz), 7.23 (1H, d, J=7.9 Hz),5.51 (2H, s), 3.64 (2H, s), 2.33 (3H, s).

1-Isopropyl-3-methoxy-benzene (Intermediate 142)

To a solution of 3-isopropyl-phenol (5.00 g, 36.2 mmols) in 50 mL ofacetone was added K₂CO₃ (7.50 g, 54.3 mmols) and iodomethane (10.3 g,72.5 mmols). The resulting solution was heated to 50° C. and stirred for18 hours, cooled to room temperature, and concentrated under reducedpressure. The residual oil was dissolved in Et₂O and washed with H₂O,saturated aqueous NaHCO₃, and saturated aqueous NaCl before being dried(MgSO₄) and concentrated under reduced pressure. The crude methyl etherwas used without further purification.

¹H NMR (CDCl₃) δ: 7.22 (1H, t, J=8.1 Hz), 6.84-6.72 (3H, m), 3.81 (3H,s), 2.88 (1H, septet, J=7.0 Hz), 1.25 (6H, d, J=7.0 Hz).

1-Bromo-2-isopropyl-4-methoxy-benzene (Intermediate 143)

A mixture of 1-isopropyl-3-methoxy-benzene (Intermediate 142, 3.50 g,23.3 mmols), molecular sieves, and silica gel in 150 mL CCl₄ was treatedwith N-bromosuccinimide (4.98 g, 28.0 mmols) at 35° C. for 18 hours. Anadditional portion of N-bromosuccinimide (830.0 mg, 4.46 mmols) wasadded and stirring continued for 6 hours. The mixture was cooled to roomtemperature, H₂O was added, and the mixture was filtered to remove thesolids. The mixture was extracted with E₂O and the combined organiclayers were washed with 10% aqueous HCl, H₂O, saturated aqueous NaHCO₃,and saturated NaCl before being dried (MgSO₄) and concentrated underreduced pressure. Column chromatography (2.5% EtOAc—hexanes) afforded4.34 g (81%) of the title compound as a pale-yellow oil.

¹H NMR (CDCl₃) δ: 7.41 (1H, d, J=8.8 Hz), 6.82 (1H, d, J=2.6 Hz), 6.61(1H, dd, J=2.6, 8.8 Hz), 3.79 (3H, s), 3.31 (1H, septet, J=6.7 Hz), 1.23(6H, d, J=6.7 Hz).

4-Bromo-3-isopropyl-phenol (Intermediate 144)

To a solution of 1-bromo-2-isopropyl-4-methoxy-benzene (Intermediate143, 2.20 g, 9.60 mmols) in 50 mL CH₂Cl₂ at −78° C. was added BBr₃ (4.81g, 19.2 mmols; 19.2 mL of a 1M solution in CH₂Cl₂). After stirring for 3hours at −78° C. the solution was warmed to 0° C. for 3 hours and thenat 25° C. for 1 hour before being quenched with H₂O. The mixture wasdiluted with Et₂O and washed with H₂O and saturated aqueous NaCl, dried(Na₂SO₄) and concentrated under reduced pressure. Column chromatography(2.5-10% EtOAc—hexanes) afforded the title compound as a colorless oil.

¹H NMR (CDCl₃) δ: 7.38 (1H, d, J=8.5 Hz), 6.79 (1H, d, J=2.9 Hz), 6.57(1H, dd, J=2.9, 8.5 Hz), 3.31 (1H, septet, J=7.0 Hz), 1.22 (6H, d, J=7.0Hz).

(4-Bromo-3-isopropyl-phenoxy)-tert-butyl-dimethyl-silane (Intermediate145)

A solution of 4-bromo-3-isopropyl-phenol (Intermediate 144, 1.13 g, 5.25mmols), chloro-tert-butyl-dimethylsilane (0.95 g, 6.30 mmols), andimidazole (428.0 mg, 6.3 mmols) in 10 mL DMF was stirred at 25° C. for 3hours. The solution was diluted with H₂O and extracted with Et₂O and thecombined organic layers were washed with H₂O, saturated aqueous NaCl,and dried (MgSO₄) before being concentrated under reduced pressure.Column chromatography (1-2% EtOAc—hexanes) afforded 1.50 g (87%) of thetitle compound as a colorless oil.

¹H NMR (CDCl₃) δ: 7.32 (1H, d, J=8.8 Hz), 6.73 (1H, d, J=3.0 Hz), 6.52(1H, dd, J=3.0, 8.8 Hz), 3.26 (1H, septet, J=6.7 Hz), 1.19 (6H, d, J=6.7Hz), 0.96 (9H, s), 0.17 (6H, s).

4-(Tert-butyl-dimethyl-silanyloxy)-2-isopropyl-benzaldehyde(Intermediate 146)

A solution of (4-bromo-3-isopropyl-phenoxy)-tert-butyl-dimethyl-silane(Intermediate 145, 1.03 g, 3.13 mmols) in 25 mL E₂O was cooled to −78°C. and treated with tert-butyllithium (401.0 mg, 6.26 mmols; 3.7 mL of a1.7M solution in pentane). After 30 minutes the reaction was quenchedwith DMF (913.0 mg, 12.5 mmols) and warmed to room temperature. Thesolution was diluted with H₂O, extracted with Et₂O and the combinedorganic layers washed with H₂O and saturated aqueous NaCl before beingdried (MgSO₄) and concentrated under reduced pressure. Columnchromatography (2% EtOAc —hexanes) afforded 480.0 mg (55%) of the titlecompound as a colorless oil.

¹H NMR (CDCl₃) δ: 10.19 (1H, s), 7.72 (1H, d, J=8.5 Hz), 6.85 (1H, d,J=2.3 Hz), 6.77 (1H, dd, J=2.3, 8.5 Hz), 3.97 (1H, septet, J=6.7 Hz),1.27 (6H, d, J=6.7 Hz), 1.00 (9H, s), 0.25 (6H, s).

4-Hydroxy-2-isopropyl-benzaldehyde (Intermediate 147)

To a solution of4-(tert-butyl-dimethyl-silanyloxy)-2-isopropyl-benzaldehyde(Intermediate 146, 880.0 mg, 3.17 mmols) in 6 mL THF at 0° C. was addedtetrabutylammonium fluoride (1.66 g, 6.33 mmols; 6.3 mL of a 1M solutionin THF). The pale-yellow solution was stirred for 30 minutes andquenched by the addition of ice cold H₂O. The mixture was extracted withEt₂O and the combined organic layers were washed with H₂O and saturatedaqueous NaCl before being dried (Na₂SO₄) and concentrated under reducedpressure. Column chromatography (20% EtOAc—hexanes) afforded 500.0 mg(96%) of the title compound as a colorless solid.

¹H NMR (CDCl₃) δ: 10.15 (1H, s), 7.79 (1H, d, J=8.5 Hz), 6.95 (1H, d,J=2.3 Hz), 6.86 (1H, dd, J=2.3, 8.5 Hz), 3.96 (1H, septet, J=6.7 Hz),1.29 (6H, d, J=6.7 Hz).

4-Formyl-3-isopropyl-phenyl 1,1,1-trifluoro-methansulfonate(Intermediate 148)

A solution of 4-hydroxy-2-isopropyl-benzaldehyde (Intermediate 147,300.0 mg, 1.83 mmol) in 10 mL of CH₂Cl₂ was cooled to 0° C. and to itwas added 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine(754.0 mg, 1.92 mmol) and triethylamine (592.0 mg, 5.85 mmols). Theresulting solution was warmed to room temperature and stirred for 4.5hours. The reaction was quenched by the addition of H₂O and the mixtureextracted with EtOAc and the combined organic layers were washed with10% aqueous HCl, saturated aqueous NaHCO₃, H₂O, and saturated aqueousNaCl. The solution was dried (MgSO₄) and concentrated under reducedpressure. The title compound was isolated by column chromatography(5-10% EtOAc—hexanes) as a colorless oil, 470.0 mg (87%).

¹H NMR (CDCl₃) δ: 10.37 (1H, s), 7.94 (1H, d, J=8.5 Hz), 7.33 (1H, d,J=2.3 Hz), 7.26 (1H, dd, J=2.3, 8.5 Hz), 4.00 (1H, septet, J=6.7 Hz),1.33 (6H, d, J=6.7 Hz),

4-Hydroxymethyl-3-isopropyl-phenyl 1,1,1-trifluoro-methansulfonate(Intermediate 149)

To a solution of 4-formyl-3-isopropyl-phenyl1,1,1-trifluoro-methansulfonate (Intermediate 148, 540.0 mg, 1.82 mmols)in 7 mL MeOH at 0° C. was added NaBH₄ (72.0 mg, 1.91 mmols). Afterstirring 2 hours at 0° C. the reaction was carefully quenched with H₂Oand extracted with Et₂O. The combined organic layers were washed withH₂O and saturated aqueous NaCl, dried (MgSO₄), and concentrated underreduced pressure. The title compound was isolated by columnchromatography (5-10% EtOAc—hexanes) as a colorless oil, 355.0 mg (90%).

¹H NMR (CDCl₃) δ: 7.45 (1H, d, J=8.5 Hz), 7.17 (1H, d, J=2.7 Hz), 7.08(1H, dd, J=2.7, 8.5 Hz), 4.74 (2H, d, J=5.3 Hz), 3.21 (1H, septet, J=7.0Hz), 2.12 (1H, t, J=5.3 Hz), 1.24 (6H, d, J=7.0 Hz).

4-( Tert-butyl-dimethyl-silanyloxymethyl)-3-isopropyl-phenyl1,1,1,-trifluoro-methansulfonate (Intermediate 150)

A solution of 4-hydroxymethyl-3-isopropyl-phenyl1,1,1-trifluoro-methansulfonate (Intermediate 149, 760.0 mg, 2.55mmols), chloro-tert-butyl-dimethylsilane (470.0 mg, 3.18 mmols), andimidazole (225.0 mg, 3.25 mmols) in 6 mL DMF was stirred at 25° C. for17 hours. The solution was diluted with H₂O and extracted with Et₂O andthe combined organic layers were washed with 10% aqueous HCl, saturatedaqueous NaHCO₃, H₂O, and saturated aqueous NaCl, and dried (MgSO₄)before being concentrated under reduced pressure. Column chromatography(2-5% EtOAc—hexanes) afforded 970.0 mg (92%) of the title compound as acolorless oil.

¹H NMR (CDCl₃) δ: 7.49 (1H, d, J=8.5 Hz), 7.10 (1H, d, J=2.3 Hz), 7.06(1H, dd, J=2.3, 8.5 Hz), 4.75 (2H, s), 3.10 (1H, septet, J=6.7 Hz), 1.21(6H, d, J=6.7 Hz), 0.93 (9H, s), 0.10 (6H, s).

1-(Tert-butyl-dimethyl-silanyloxymethyl)-2-isopropyl-4-trimethylsilanylethynyl-benzene(Intermediate 151)

To a solution of4-(tert-butyl-dimethyl-silanyloxymethyl)-3-isopropyl-phenyl1,1,1-trifluoro-methansulfonate (Intermediate 150, 970.0 mg, 2.35 mmols)in triethylamine (2 mL) and 6 mL DMF was sparged with argon for 15minutes. Trimethylsilyl acetylene (1.00 g, 10.6 mmols) was then addedfollowed by dichlorobis(triphenylphosphine)palladium(II) (66.0 mg, 0.09mmol). The resulting reaction mixture was heated to 95° C. for 20 hours.The solution was cooled to room temperature and concentrated underreduced pressure. The title compound (200.0 mg, 78%) was isolated bychromatography (0-25% EtOAc—hexanes) as an orange oil.

¹H NMR (CDCl₃) δ: 7.37-7.25 (3H, m), 4.75 (2H, s), 3.08 (1H, septet,J=7.0 Hz), 1.21 (6H, d, J=7.0 Hz), 0.92 (9H, s), 0.25 (9H, s), 0.09 (6H,s).

Tert-butyl-(4-ethynyl-2-isopropyl-benzyloxy)-dimethyl-silane(Intermediate 152)

Using General Procedure E;1-(tert-butyl-dimethyl-silanyloxymethyl)-2-isopropyl-4-trimethylsilanylethynyl-benzene(Intermediate 151, 850.0 mg, 2.36 mmols) in methanol (25 mL) was treatedwith potassium carbonate (250.0 mg, 1.81 mmols) and stirred overnight atambient temperature. The crude alkyne (650 mg, 95%) was used directly inthe next reaction.

¹H NMR (CDCl₃) δ: 7.41-7.25 (3H, m), 4.77 (2H, s), 3.07 (1H, septet,J=7.0 Hz), 3.05 (1H, s), 1.22 (6H, d, J=7.0 Hz), 0.94 (9H, s), 0.11 (6H,s).

Ethyl4-[4-(tert-butyl-dimethyl-silanyloxymethyl)-3-isopropyl-phenylethynyl]-benzoate(Intermediate 153)

Using General procedure F;tert-butyl-(4-ethynyl-2-isopropyl-benzyloxy)-dimethyl-silane(Intermediate 152, 300.0 mg, 1.04 mmols) and ethyl-4-iodo benzoate(Reagent A, 287.0 mg, 1.04 mmols) in triethylamine (8 mL) was treatedwith copper(I)iodide (50.0 mg, 0.26 mmol) and sparged with argon for 5minutes. Dichlorobis(triphenylphosphine)palladium(II) (182 mg, 0.26mmol) was added and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-4% EtOAc—hexanes) afforded 310.0mg (68%) of the title compound as an orange solid.

¹H NMR (CDCl₃) δ: 8.03 (2H, d, J=8.5 Hz), 7.60 (2H, d, J=8.5 Hz),7.48-7.37 (3H, m), 4.80 (2H, s), 4.39 (2H, q, J=7.1 Hz), 3.14 (1H,septet, J=6.8 Hz), 1.40 (3H, t, J=7.1 Hz), 1.27 (6H, d, J=6.8 Hz), 0.96(9H, s), 0.12 (6H, s).

Methyl{4-[4-(tert-butyl-dimethyl-silanyloxymethyl)-3-isopropyl-phenylethynyl]-phenyl}-acetate(Intermediate 154)

Using General Procedure F;tert-butyl-(4-ethynyl-2-isopropyl-benzyloxy)-dimethyl-silane(Intermediate 152, 355.0 mg, 1.26 mmols) andmethyl-(4-iodophenyl)-acetate (Reagent B, 349.0 mg, 1.26 mmols) intriethylamine (8 mL) was treated with copper(I)iodide (60.0 mg, 0.32mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)palladium(II) (222 mg, 0.32 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-5% EtOAc—hexanes) afforded 288.0mg (66%) of the title compound as an orange oil.

¹H NMR (CDCl₃) δ: 7.49 (2H, d, J=8.5 Hz), 7.43-7.35 (3H, m), 7.25 (2H,J=8.5 Hz), 4.77 (2H, s), 3.69 (3H, s), 3.63 (2H, s), 3.11 (1H, septet,J=6.7 Hz), 1.25 (6H, d, J=6.7 Hz), 0.94 (9H, s), 0.10 (6H, s).

Ethyl[4-(4-hydroxymethyl-3-isopropyl-phenylethynyl)-benzoate (Compound122, General Formula 6)

To a solution of ethyl4-[4-(tert-butyl-dimethyl-silanyloxymethyl)-3-isopropyl-phenylethynyl]-benzoate(Intermediate 153, 310.0 mg, 0.71 mmol) in 4 mL THF at 0° C. was addedtetrabutylammonium fluoride (371.0 mg, 1.42 mmols; 1.4 mL of a 1Msolution in THF). The pale-yellow solution was stirred for 10 minutesand quenched by the addition of ice cold H₂O. The mixture was extractedwith Et₂O and the combined organic layers were washed with H₂O andsaturated aqueous NaCl before being dried (Na₂SO₄) and concentratedunder reduced pressure. Column chromatography (20-30% EtOAc—hexanes)afforded 200.0 mg (87%) of the title compound as a colorless solid.

¹H NMR (CDCl₃) δ: 7.98 (2H, d, J=8.5 Hz), 7.58 (2H, d, J=8.5 Hz), 7.48(1H, s), 7.35 (2H, m), 4.71 (2H, s), 4.35 (2H, q, J=7.1 Hz), 3.19 (1H,septet, J=7.0 Hz), 2.51 (1H, s), 1.39 (3H, t, J=7.1 Hz), 1.25 (6H, d,J=7.0 Hz).

Methyl[4-(4-hydroxymethyl-3-isopropyl-phenylethynyl)-phenyl]-acetate(Compound 123, General Formula 6)

To a solution ofmethyl{4-[4-(tert-butyl-dimethyl-silanyloxymethyl)-3-isopropyl-phenylethynyl]-phenyl}-acetate(Intermediate 154, 288.0 mg, 0.66 mmol) in 5 mL THF at 0° C. was addedtetrabutylammonium fluoride (471.0 mg, 1.80 mmols; 1.8 mL of a 1Msolution in THF). The pale-yellow solution was stirred for 15 minutesand quenched by the addition of ice cold H₂O. The mixture was extractedwith Et₂O and the combined organic layers were washed with H₂O andsaturated aqueous NaCl before being dried (Na₂SO₄) and concentratedunder reduced pressure. Column chromatography (5-10% EtOAc—hexanes)afforded 180.0 mg (85%) of the title compound as a colorless solid.

¹H NMR (CDCl₃) δ: 7.48 (3H, m), 7.32 (2H, m), 7.24 (2H, d, J=8.5 Hz),4.69 (2H, s), 3.68 (3H, s), 3.62 (2H, s), 3.18 (1H, septet, J=7.0 Hz),2.21 (1H, s), 1.25 (6H, d, J=7.0 Hz).

Ethyl[4-(4-bromomethyl-3-isopropyl-phenylethynyl)-benzoate (Intermediate155)

A solution of ethyl[4-(4-hydroxymethyl-3-isopropyl-phenylethynyl)-benzoate (Compound 122,200.0 mg, 0.62 mmol) and triphenylphosphine (211.0 mg, 0.81 mmol) in 5mL CH₂Cl₂ was cooled to 0° C. and N-bromosuccinimide (144.0 mg, 0.81mmol) was added in 5 portions over 20 minutes. The solution was warmedto 25° C. and stirred for 17 hours. The reaction was quenched by theaddition of dilute aqueous NaHCO₃. The resulting mixture was extractedwith Et₂O and the combined organic layers were washed with H₂O andsaturated aqueous NaCl before being dried (Na₂SO₄) and concentratedunder reduced pressure. The title compound, 220.0 mg (93%), was isolatedby column chromatography (5% EtOAc—hexanes) as a pale-yellow solid.

¹H NMR (CDCl₃) δ: 8.03 (2H, d, J=8.2 Hz), 7.59 (2H, d, J=8.2 Hz), 7.48(1H, s), 7.31 (2H, m) 4.55 (2H, s), 4.39 (2H, q, J=7.1 Hz), 3.29 (1H,septet, J=7.0 Hz), 1.40 (3H, t, J=7.1 Hz), 1.30 (6H, d, J=7.0 Hz).

Methyl[4-(4-bromomethyl-3-isopropyl-phenylethynyl)-phenyl]-acetate(Intermediate 156)

A solution of methyl[4-(4-hydroxymethyl-3-isopropyl-phenylethynyl)-phenyl]-acetate (Compound123, 180.0 mg, 0.56 mmol) and triphenylphosphine (190.0 mg, 0.73 mmol)in 5 mL CH₂Cl₂ was cooled to 0° C. and N-bromosuccinimide (130.0 mg,0.73 mmol) was added in 5 portions over 20 minutes. The solution waswarmed to 25° C. and stirred for 17 hours. The reaction was quenched bythe addition of dilute aqueous NaHCO₃. The resulting mixture wasextracted with Et₂O and the combined organic layers were washed with H₂Oand saturated aqueous NaCl before being dried (Na₂SO₄) and concentratedunder reduced pressure. The title compound, 212.0 mg (98%), was isolatedby column chromatography (5-10% EtOAc—hexanes) as a pale-yellow oil.

¹H NMR (CDCl₃) δ: 7.48 (3H, m), 7.28 (4H, m), 4.55 (2H, s), 3.69 (3H,s), 3.63 (2H, s), 3.28 (1H, septet, J=7.0 Hz), 1.30 (6H, d, J=7.0 Hz).

Ethyl[4-(4-imidazol-1-yl-methyl-3-isopropyl-phenylethynyl)-phenyl]-benzoate(Compound 124, General Formula 6)

A solution of ethyl[4-(4-bromomethyl-3-isopropyl-phenylethynyl)-benzoate (Intermediate 155,120.0 mg, 0.31 mmol) and 1-acetylimidazole (36.0 mg, 0.33 mmol) in 5 mLCH₃CN was heated at 65° C. for 4 hours and then at 55° C. for 16 hours.The solution was cooled to room temperature, diluted with H₂O and madebasic by addition of Na₂CO₃, and extracted with EtOAc. The combinedorganic layers were washed with H₂O and saturated aqueous NaCl, dried(MgSO₄), and concentrated under reduced pressure. Column chromatography(1% Et₃N in 5% MeOH-EtOAc) afforded 75.0 mg (65%) of the title compoundas a colorless solid.

¹H NMR (CDCl₃) δ: 8.03 (2H, d, J=8.5 Hz), 7.60 (2H, d, J=8.5 Hz), 7.53(1H, d, J=1.5 Hz), 7.49 (1H, s), 7.35 (1H, dd, J=1.5, 7.9 Hz), 7.09 (1H,bs), 6.98 (1H, d, J=7.9 Hz), 6.85 (1H, bs), 5.19 (2H, s), 4.39 (2H, q,J=7.1 Hz), 3.08 (1H, septet, J=6.8 Hz), 1.40 (3H, t, J=7.1 Hz), 1.20(6H, d, J=6.8 Hz).

Methyl[4-(4-imidazol-1-yl-methyl-3-isopropyl-phenylethynyl)-phenyl]-acetate(Compound 125, General Formula 6)

A solution of methyl[4-(4-bromomethyl-3-isopropyl-phenylethynyl)-phenyl]-acetate(Intermediate 156, 72.0 mg, 0.19 mmol) and 1-acetylimidazole (22.0 mg,0.20 mmol) in 5 mL CH₃CN was heated at 65° C. for 8 h and then at 55° C.for 16 hours. The solution was cooled to room temperature, diluted withH₂O and made basic by addition of Na₂CO₃, and extracted with EtOAc. Thecombined organic layers were washed with H₂O and saturated aqueous NaCl,dried (MgSO₄), and concentrated under reduced pressure. Columnchromatography (0.5% Et₃N in 5% MeOH-EtOAc) afforded 40.0 mg (58%) ofthe title compound as a colorless solid.

¹H NMR (CDCl₃) δ: 7.49 (4H, m), 7.33 (1H, dd, J=1.5, 7.9 Hz), 7.28 (2H,d, J=8.5 Hz), 7.08 (1H, t, J=1.2 Hz), 6.95 (1H, d, J=7.9 Hz), 6.84 (1H,t, J=1.2 Hz), 5.17 (2H, s), 3.70 (3H, s), 3.64 (2H, s), 3.06 (1H,septet, J=6.8 Hz), 1.20 (6H, d, J=6.8 Hz).

[4-(4-Imidazol-1-yl-methyl-3-isopropyl-phenylethynyl)-phenyl]-benzoicacid (Compound 126, General Formula 6)

Using General Procedure I; a solution of ethyl[4-(4-imidazol-1-ylmethyl-3-isopropyl-phenylethynyl)-phenyl]-benzoate(Compound 124, 75.0 mg, 0.20 mmol) in ethanol (4 mL) and tetrahydrofuran(1 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1Naqueous solution) and stirred overnight at room temperature. Work-upafforded 68.0 mg (88%) of the title compound as a colorless solid.

¹H NMR (d₄-MeOH) δ: 9.01 (1H, s), 8.01 (2H, d, J=8.2 Hz), 7.63-7.57 (5H,m), 7.44 (1H, d, J=7.9 Hz), 7.29 (1H, d, J=7.9 Hz), 5.59 (2H, s), 3.17(1H, septet, J=6.8 Hz), 1.20 (6H, d, J=6.8 Hz).

[4-(4-Imidazol-1-yl-methyl-3-isopropyl-phenylethynyl)-phenyl]-aceticacid (Compound 127, General Formula 6)

Using General Procedure I; a solution of methyl[4-(4-imidazol-1-ylmethyl-3-isopropyl-phenylethynyl)-phenyl]-acetate(Compound 125, 40.0 mg, 0.11 mmol) in ethanol (4 mL) and tetrahydrofuran(1 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1Naqueous solution) and stirred overnight at room temperature. Work-upafforded 22.0 mg (52%) of the title compound as a colorless solid.

¹H NMR (d₄-MeOH) δ: 9.02 (1H, bs), 7.62 (1H, t, J=1.4 Hz), 7.58 (2H, m),7.49 (2H, d, J=8.2 Hz), 7.43 (1H, dd, J=1.5, 7.9 Hz), 7.31 (3H, m), 5.58(2H, s), 3.68 (2H, s), 3.16 (1H, septet, J=6.7 Hz), 1.18 (6H, d, J=6.7Hz).

4-Bromo-N-cyclopropyl-2-methyl-benzamide (Intermediate 157)

A solution of 4-bromo-2-methylbenzoic acid and SOCl₂ was refluxed for 3hours, cooled to room temperature and concentrated under reducedpressure. The residue was dissolved in 30 mL CH₂Cl₂ and combined withcyclopropyl amine (810.0 mg, 14.3 mmols) and pyridine (2.05 g, 26.0mmols). The solution was stirred for 18 hours and then diluted withEtOAc before being washed with 5% aqueous HCl, saturated NaHCO₃, andsaturated aqueous NaCl. The solution was dried (MgSO₄) and concentratedunder reduced pressure leaving the title compound as a colorless solid.

¹H NMR (CDCl₃) δ: 7.34 (1H, d, J=2.3 Hz), 7.28 (1H, dd, J=2.3, 8.2 Hz),7.13 (1H, d, J=8.2 Hz), 6.10 (1H, bs), 2.85 (1H, m), 2.37 (3H, s), 0.85(2H, m), 0.59 (2H, m).

(4-Bromo-2-methyl-benzyl)-cyclopropyl-amine (Intermediate 158)

To a solution of 4-bromo-N-cyclopropyl-2-methyl-benzamide (Intermediate157, 1.81 g, 7.12 mmols) in THF (12 mL) was added BH₃.SMe₂ (1.08 g,14.24 mmols). The solution was heated to 60° C. for 6 hours, cooled toroom temperature and carefully treated with saturated aqueous Na₂CO₃ (30mL) and stirred for 17 hours. This mixture was extracted with EtOAc andthe combined organic layers were washed with H₂O, saturated aqueous NaClbefore being dried (MgSO₄) and concentrated under reduced pressure. Thetitle compound was isolated by column chromatography (10-15%EtOAc—hexanes).

¹H NMR (CDCl₃) δ: 7.26 (2H, m), 7.12 (1H, d, J=7.9 Hz), 3.76 (2H, s),2.31 (3H, s), 2.14 (1H, m), 0.44 (2.H, m), 0.36 (2H, m).

(4-Bromo-2-methyl-benzyl)-cyclopropyl-ethyl-amine (Intermediate 159)

A mixture of (4-bromo-2-methyl-benzyl)-cyclopropyl-amine (Intermediate158, 600.0 mg, 2.49 mmols), ethyl iodide (1.56 g, 10.0 mmols), and K₂CO₃(690.0 mg, 5.00 mmols) in 10 mL acetone was heated at 60° C. for 18hours. The mixture was cooled to room temperature, diluted with H₂O, andextracted with EtOAc. The combined organic layers were washed with H₂Oand saturated aqueous NaCl before being dried (MgSO₄) and concentratedunder reduced pressure. The title compound was isolated by columnchromatography (2.5% EtOAc—hexanes).

¹H NMR (CDCl₃) δ: 7.23 (2H, m), 7.12 (1H, d, J=7.6 Hz), 3.62 (2H, s),2.56 (2H, q, J=7.3 Hz), 2.29 (3H, s), 1.75 (1H, m), 1.04 (3H, t, J=7.3Hz), 0.39 (2H, m), 0.30 (2H, m).

Cyclopropyl-ethyl-(2-methyl-4-trimethylsilanylethynyl-benzyl)-amine(Intermediate 160)

Using General Procedure D;(4-bromo-2-methyl-benzyl)-cyclopropyl-ethyl-amine (Intermediate 159,620.0 mg, 2.31 mmols) in triethylamine (8 mL) was treated withcopper(I)iodide (44.0 mg, 0.23 mmol) and then sparged with argon for 15minutes. Trimethylsilylacetylene (1.04 g, 10.6 mmols) was then addedfollowed by dichlorobis-(triphenylphosphine)palladium(II) (162.0 mg,0.23 mmol). The resulting reaction mixture was heated to 70° C. for 5days. The title compound (650.0 mg, 98%) was isolated by chromatography(1-4% EtOAc—hexanes).

¹H NMR (CDCl₃) δ: 7.32 (1H, s), 7.20 (2H, m), 3.65 (2H, s), 2.55 (2H, q,J=7.3 Hz), 2.28 (3H, s), 1.74 (1H, m), 1.03 (3H, t, J=7.3 Hz), 0.36 (2H,m), 0.27 (2H, m), 0.24 (9H, s).

Cyclopropyl-ethyl-(4-ethynyl-2-methyl-benzyl)-amine (Intermediate 161)

Using General Procedure E;cyclopropyl-ethyl-(2-methyl-4-trimethylsilanylethynyl-benzyl)-amine(Intermediate 160, 650.0 mg, 2.30 mmols) in methanol (10 mL) was treatedwith potassium carbonate (100.0 mg, 0.72 mmol) and stirred overnight atambient temperature. The crude alkyne (495 mg, 99%) was used directly inthe next reaction.

¹H NMR (CDCl₃) δ: 7.32 (1H, s), 7.21 (2H, m), 3.66 (2H, s), 3.01 (1H,s), 2.56 (2H, q, J=7.3 Hz), 2.29 (3H, s), 1.76 (1H, m), 1.04 (3H, t,J=7.3 Hz), 0.40 (2H, m), 0.29 (2H, m).

Ethyl4-{4-[(cyclopropyl-ethyl-amino)-methyl]-3-methyl-phenylethynyl}-benzoate(Compound 128, General Formula 6)

Using General Procedure F;cyclopropyl-ethyl-(4-ethynyl-2-methyl-benzyl)-amine (Intermediate 161,190.0 mg, 0.89 mmol) and ethyl-4-iodo benzoate (Reagent A, 245.0 mg,0.89 mmol) in triethylamine (5 mL) was treated with copper(I)iodide(56.0 mg, 0.30 mmol) and sparged with argon for 15 minutes.Dichlorobis(triphenylphosphine)-palladium(II) (208 mg, 0.30 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (3-5% EtOAc—hexanes) afforded thetitle compound.

¹H NMR (CDCl₃) δ: 8.01 (2H, d, J=8.2 Hz), 7.56 (2H, d, J=8.2Hz),7.31-7.24 (3H, m), 4.38 (2H, q, J=7.1 Hz), 3.68 (2H, s), 2.58 (2H,q, J=7.3 Hz), 2.32 (3H, s), 1.77 (1H, m), 1.39 (3H, t, J=7.1 Hz), 1.05(3H, t, J=7.3 Hz), 0.39 (2H, m), 0.31 (2H, m).

Methyl(4-{4-[(cyclopropyl-ethyl-amino)-methyl]-3-methyl-phenylethynyl}-phenyl)-acetate)(Compound 129, General Formula 6)

Using General Procedure F;cyclopropyl-ethyl-(4-ethynyl-2-methyl-benzyl)-amine (Intermediate 161,300.0 mg, 1.41 mmols) and methyl-4-iodophenyl)-acetate (Reagent B, 388.0mg, 1.41 mmols) in triethylamine (8 mL) was treated with copper(I)iodide(67.0 mg, 0.35 mmol) and sparged with argon for 15 minutes.Dichlorobis(triphenylphosphine)palladium(II) (246 mg, 0.35 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (5-7% EtOAc—hexanes) afforded 270.0mg (53%) of the title compound as a pale-yellow oil.

¹H NMR (CDCl₃) δ: 7.47 (2H, d, J=7.9 Hz), 7.30-7.22 (5H, m), 3.70 (3H,s), 3.68 (2H, s), 3.63 (2H, s), 2.58 (2H, q, J=7.3 Hz), 2.32 (3H, s),1.77 (1H, m), 1.05 (3H, t, J=7.3 Hz), 0.39 (2H, m), 0.30 (2H, m).

4-{4-[(Cyclopropyl-ethyl-amino)-methyl]-3-methyl-phenylethynyl}-benzoicacid: (Compound 130, General Formula 6)

Using General Procedure I; a solution of ethyl4-{4-[(cyclopropyl-ethyl-amino)-methyl]-3-methyl-phenylethynyl}-benzoate(Compound 128, 130.0 mg, 0.36 mmol) in ethanol (5 mL) andtetrahydrofuran (5 mL) was treated with NaOH (360.0 mg, 9.0 mmols, 3.0mL of a 3N aqueous solution) and stirred overnight at room temperature.Work-up afforded 115.0 mg (96%) of the title compound as a colorlesssolid.

¹H NMR (d₆-acetone) δ: 8.05 (2H, d, J=8.2 Hz), 7.64 (2H, d, J=8.2 Hz),7.32 (3H, m), 3.73 (2H, s), 2.59 (2H, q, J=7.3 Hz), 2.35 (3H, s), 1.83(1H, m), 1.05 (3H, t, J=7.3 Hz), 0.38 (2H, m), 0.27 (2H, m) .

(4-{4-[(Cyclopropyl-ethyl-amino)-methyl]-3-methyl-phenylethynyl}-phenyl)-aceticacid (Compound 131, General Formula 6)

Using General Procedure I; a solution of methyl(4-{4-[(cyclopropyl-ethyl-amino)-methyl]-3-methyl-phenylethynyl}-phenyl)-acetate(Compound 129, 140.0 mg, 0.39 mmol) in ethanol (5 mL) andtetrahydrofuran (5 mL) was treated with NaOH (360.0 mg, 9.0 mmols, 3.0mL of a 3N aqueous solution) and stirred overnight at room temperature.Work-up followed by HPLC (Partisil-10 pac 10% H₂O—CH₃CN) afforded thetitle compound.

¹H NMR (CDCl₃) δ: 7.45 (2H, d, J=8.2 Hz), 7.25 (5H, m), 4.16 (2H, m),3.82 (2H, s), 3.56 (2H, s), 2.75 (2H, q, J=7.3 Hz), 2.30 (3H, s), 1.86(1H, m), 1.14 (3H, t, J=7.3 Hz), 0.54 (2H, m), 0.46 (2H, m).

Ethyl{4-(4-cyclopropylaminomethyl-3-isopropyl-phenylethynyl}-benzoate(Compound 132, General Formula 6)

A solution of ethyl[4-(4-bromomethyl-3-isopropyl-phenylethynyl)-benzoate (Intermediate 155,110.0 mg, 0.29 mmol) and cyclopropylamine (420.0 mg, 7.4 mmols) in EtOH(5 mL) was stirred at 25° C. for 6 hours and then concentrated underreduced pressure. The residue was dissolved in EtOAc and washed withsaturated aqueous NaHCO₃, H₂O and saturated aqueous NaCl. The solutionwas dried (MgSO₄) and concentrated under reduced pressure to give 103 mg(99%) of the title compound as an orange oil.

¹H NMR (CDCl₃) δ: 8.01 (2H, d, J=8.5 Hz), 7.59 (2H, d, J=8.5 Hz), 7.47(1H, s), 7.30 (2H, m), 4.38 (2H, q, J=7.1 Hz), 3.89 (2H, s), 3.26 (1H,septet, J=7.0 Hz), 2.17 (1H, m), 1.40 (3H, t, J=7.1 Hz), 1.26 (6H, d,J=7.0 Hz), 0.45 (2H, m), 0.39 (2H, m).

Ethyl4-{4-[(cyclopropyl-ethyl-amino)-methyl]-3-isopropyl-phenylethynyl}-benzoate(Compound 133, General Formula 6)

To a solution ofethyl{4-(4-cyclopropylaminomethyl-3-isopropyl-phenylethynyl}-benzoate(Compound 132, 103.0 mg, 0.29 mmol) in 6 mL of acetone was added ethyliodide (67.0 mg, 0.43 mmol) and K₂CO₃ (79.0 mg, 0.57 mmol). The mixturewas stirred at 60° C. for 6 hours, cooled to room temperature andquenched by the addition of H₂O. The mixture was extracted with EtOAcand the combined organic layers were washed with H₂O and saturatedaqueous NaCl before being dried (MgSO₄) and concentrated under reducedpressure. Column chromatography (4-5% EtOAc—hexanes) afforded 68.0 mg(59%) of the title compound.

¹H NMR (CDCl₃) δ: 8.01 (2H, d, J=8.6 Hz), 7.58 (2H, d, J=8.6 Hz), 7.44(1H, s), 7.28 (2H, m), 4.39 (2H, q, J=7.1 Hz), 3.73 (2H, s), 3.55 (1H,septet, J=6.6 Hz), 2.57 (2H, q, J=7.3 Hz), 1.75 (1H, m), 1.40 (3H, t,J=7.1 hz), 1.22 (6H, d, J=6.6 Hz), 1.05 (3H, t, J=7.3 Hz), 0.37 (2H, m),0.28 (2H, m).

4-{4-[(Cyclopropyl-ethyl-amino)-methyl]-3-isopropyl-phenylethynyl}-benzoicacid (Compound 134, General Formula 6)

Using General Procedure I; a solution of ethyl4-{4-[(cyclopropyl-ethyl-amino)-methyl]-3-isopropyl-phenylethynyl}-benzoate(Compound 133, 68.0 mg, 0.17 mmol) in ethanol (3 mL) and tetrahydrofuran(3 mL) was treated with NaOH (600.0 mg,15.0 mmols, 3.0 mL of a 5Naqueous solution) and stirred overnight at room temperature and then at55° C. for 9 hours. Work-up followed by crystallization of the solidresidue from hot CH₃CN afforded 45.0 mg (72%) of the title compound as apale-yellow solid.

¹H NMR (d₆-acetone) δ: 8.05 (2H, d, J=8.1 Hz), 7.66 (2H, d, J=8.1 Hz),7.49 (1H, s), 7.32 (2H, m), 3.78 (2H, s), 3.44 (1H, septet, J=6.7 Hz),2.59 (2H, q, J=7.3 Hz), 1.80 (1H, m), 1.21 (6H, d, J=6.7 Hz), 1.05 (3H,t, J=7.3 Hz), 0.40 (2H, m), 0.26 (2H, m).

Methyl[4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-phenyl]-acetate(Compound 4, General Formula 8)

Using General Procedure F;6-ethynyl-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 13,190.0 mg, 0.96 mmol) and methyl-4-iodophenyl)-acetate (Reagent B, 245.0mg, 0.96 mmol) in triethyl amine (8 mL) was treated with copper(I)iodide(46 mg, 0.24 mmol) and sparged with argon for 15 minutes.Dichlorobis(triphenylphosphine)palladium(II) (168 mg, 0.24 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (10-20% EtOAc—hexanes) afforded 250.0mg (75%) of the title compound as a pale-yellow solid.

¹H NMR (CDCl₃) δ: 7.99 (1H, d, J=7.9 Hz), 7.57 (1H, d, J=1.5 Hz), 7.51(2H, d, J=8.5 Hz), 7.43 (1H, dd, J=1.5, 7.9 Hz), 7.29 (2H, d, J=8.5 Hz),3.70 (3H, s), 3.65 (2H, s), 2.73 (2H, t, J=7.0 Hz), 2.04 (2H, t, J=7.0Hz), 1.41 (6H, s).

Methyl[4-(5-hydroxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-phenyl]-acetate(Compound 135, General Formula 4)

To a solution of methyl[4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-phenyl]-acetate(Compound 4) in 5 mL MeOH at 0° C. was added NaBH₄ (18.0 mg, 0.48 mmol).The reaction was stirred at 0° C. for 2 hours and then quenched by theaddition of H₂O. The solution was diluted with Et₂O and washed with H₂Oand saturated aqueous NaCl before being dried (MgSO₄) and the solventswere removed under reduced pressure. Column chromatography (20-40%EtOAc—hexanes) afforded 140.0 mg (87%) of the title compound as acolorless oil.

¹H NMR (CDCl₃) δ: 7.49 (3H, m), 7.39 (1H, d, J=7.9 Hz), 7.31 (1H, dd,J=1.5, 7.9 Hz), 7.25 (2H, d, J=8.2 Hz), 4.58 (1H, bs), 3.68 (3H, s),3.62 (2H, s), 2.05 (1H, m), 1.79 (2H, m), 1.60 (1H, m), 1.33 (3H, s),1.26 (3H, s).

Methyl[4-(5-imidazol-1-yl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl)-phenyl]-acetate(Compound 136, General Formula 4)

A solution of methyl[4-(5-hydroxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl)-phenyl]-acetate(Compound 135, 140.0 mg, 0.40 mmol) and carbonyldiimidazole (136.0 mg,0.84 mmol) in 5 mL THF was heated to 65° C. for 48 hours. The solutionwas cooled to room temperature and concentrated under reduced pressure.The residue was dissolved in Et₂O and washed with 5% aqueous NaOH, H₂O,and saturated aqueous NaCl before being dried (Na₂SO₄) and concentratedunder reduced pressure. Column chromatography (5% MeOH—CH₂Cl₂) afforded50.0 mg (31%) of the title compound as a colorless solid.

¹H NMR (CDCl₃) δ: 7.57 (1H, d, J=1.5 Hz), 7.52-7.45 (3H, m), 7.27 (3H,m), 7.08 (1H, s), 6.81 (2H, m), 5.30 (1H, t, J=5.8 Hz), 3.71 (3H, s),3.65 (2H, s), 2.20 (2H, m), 1.75 (2H, m), 1.40 (3H, s), 1.36 (3H, s).

[4-(5-Imidazol-1-yl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-phenyl]-aceticacid (Compound 137, General Formula 4)

Using General Procedure I; a solution of methyl[4-(5-imidazol-1-yl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-ethylnyl)-phenyl]-acetate(Compound 136, 50.0 mg, 0.13 mmol) in ethanol (4 mL) was treated withNaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirredovernight at room temperature. Work-up afforded 40.0 mg (83%) of thetitle compound as a pale-orange solid.

¹H NMR (d₄-MeOH) δ: 8.93 (1H, s), 7.68 (1H, s), 7.61 (1H, s), 7.54 (1H,s), 7.47 (2H, d, J=8.2 Hz), 7.31 (3H, m), 6.95 (1H, d, J=8.2 Hz), 5.83(1H, t, J=5.8 Hz), 3.68 (1H, s), 3.63 (1H, s), 2.38 (1H, m), 2.26 (1H,m), 1.76 (2H, m), 1.45 (3H, s), 1.36 (3H, s).

Ethyl[4-(5-imidazol-1-yl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-benzoate(Compound 138, General Formula 4)

A solution of ethyl[4-(5-hydroxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-benzoate(180.0 mg, 0.52 mmol) and carbonyldiimidazole (176.0 mg, 1.08 mmol) in 5mL THF was heated to 65° C. for 21 hours. The solution was cooled toroom temperature and concentrated under reduced pressure. The residuewas dissolved in Et₂O and washed with 55 aqueous NaOH, H₂O, andsaturated aqueous NaCl before being dried (Na₂SO₄) and concentratedunder reduced pressure. Column chromatography (5% MeOH—CH₂Cl₂) afforded50.0 mg (24%) of the title compound as a colorless solid.

¹H NMR (CDCl₃) δ: 8.03 (2H, d, J=7.9 Hz), 7.59 (3H, m), 7.46 (1H, s),7.29 (1H, dd, J=1.5, 8.3 Hz), 7.09 (1H, s), 6.82 (1H, d, J=8.2 Hz), 6.81(1H, s), 5.31 (1H, t, J=5.8 Hz), 4.39 (2H, q, J=7.1 Hz), 2.20 (2H, m),1.75 (2H, m), 1.40 (9H, m).

[4-(5-Imidazol-1-yl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-benzoicacid (Compound 139, General Formula 4)

Using General Procedure I; a solution of ethyl[4-(5-imidazol-1-yl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-benzoate(Compound 138, 50.0 mg, 0.13 mmol) in ethanol (3 mL) and tetrahydrofuran(1 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1Naqueous solution) and stirred overnight at room temperature. Work-upafforded 40.0 mg (87%) of the title compound as a colorless solid.

¹H NMR (d₄-MeOH) δ: 8.92 (1H, s), 8.04 (2H, d, J=8.2 Hz), 7.74 (1H, d,J=1.5 Hz), 7.62 (3H, m), 7.57 (1H, t, J=1.5 Hz), 7.38 (1H, dd, J=1.5,7.9 Hz), 6.97 (1H, d, J=7.9 Hz), 5.83 (1H, t, J=5.8 Hz), 2.33 (2H, m),1.78 (2H, m), 1.47 (3H, s), 1.39 (3H, s).

2-Isopropyl-4-trifluoromethanesulfonyloxy-benzyl acetate (Intermediate162)

To a solution of 4-hydroxymethyl-3-isopropylphenyl1,1,1-trifluoromethanesulfonate (Intermediate 149, 190.0 mg, 0.64 mmol)in 5 mL CH₂Cl₂ was added acetyl chloride (75.0 mg, 0.96 mmol) andpyridine(101.0 mg, 1.38 mmols). After stirring for 3 hours at 25° C. thereaction was quenched by the addition of H₂O and the resulting mixtureextracted with EtOAc. The combined organic layers were washed with H₂Oand saturated aqueous NaCl, dried (MgSO₄) and concentrated under reducedpressure. The title compound, 182 mg (84%), was isolated from theresidual oil by column chromatography (5-10% EtOAc—hexanes) as acolorless oil.

¹H NMR (CDCl₃) δ: 7.43 (1H, d, J=8.7 Hz), 7.19 (1H, d, J=2.7 Hz), 7.09(1H, dd, J=2.7, 8.5 Hz), 5.17 (2H, s), 3.18 (1H, septet, J=6.7 Hz), 2.10(3H, s), 1.26 (6H, d, J=6.7 Hz).

4-Isopropenyloxymethyl-3-isopropyl-phenyl1,1,1-trifluoromethanesulfonate (Intermediate 163)

Using General Procedure 1;2-isopropyl-4-trifluoromethanesulfonyloxy-benzyl acetate (Intermediate162, 182.0 mg, 0.54 mmols), and 1.1 mL of Tebbe's Reagent (159.0 mg,0.56 mmols) afforded 130.0 mg (72%) of the title compound as a colorlessoil after column chromatography (2-5% EtOAc—hexanes).

¹H NMR (CDCl₃) δ: 7.43 (1H, d, J=8.5 Hz), 7.18 (1H, d, J=2.6 Hz), 7.09(1H, dd, J=2.6, 8.5 Hz), 4.75 (2H, s), 3.98 (2H, s), 3.12 (1H, septet,J=6.7 Hz), 1.88 (3H, s), 1.25 (6H, d, J=Hz).

3-Isopropyl-4-(1-methyl-cyclopropoxymethyl)-phenyl1,1,1-trifluoromethanesulfonate (Intermediate 164)

Using General Procedure 2; 4-isopropenyloxymethyl-3-isopropylphenyl1,1,1-trifluoromethanesulfonate (Intermediate 163, 130.0 mg, 0.39 mmol),Et₂Zn (272.0 mg, 2.2 mmols), and CH₂I₂ (702.0 mg, 2.6 mmols) in 3.0 mLEt₂O afforded 120.0 mg (89%) of the title compound as a colorless oilafter column chromatography (4-5% EtOAc—hexanes).

¹H NMR (CDCl₃) δ: 7.39 (1H, d, J=8.5 Hz), 7.13 (1H, d, J=2.7 Hz), 7.05(1H, dd, J=2.7, 8.5 Hz), 4.54 (2H, s), 3.16 (1H, septet, J=6.7 Hz), 1.47(3H, s), 1.24 (6H, d, J=6.7 Hz), 0.86 (2H, m), 0.48 (2H, m).

[3-Isopropyl-4-(1-methyl-cyclopropoxymethyl)-phenylethynyl]-trimethylsilane(Intermediate 165)

Using General Procedure D;3-isopropyl-4-(1-methyl-cyclopropoxymethyl)-phenyl1,1,1-trifluoromethanesulfonate (Intermediate 164, 120.0 mg, 0.34 mmol)in triethylamine (2 mL) and anhydrous DMF (5 mL) was sparged with argonfor 5 minutes. Trimethylsilyl acetylene (700.0 mg, 0.71 mmol) was thenadded followed by dichlorobis(triphenylphosphine)palladium(II) (24.0 mg,0.03 mmol). The resulting reaction mixture was heated to 95° C. for 60hours. The title compound 110.0 mg, (99%) was isolated by chromatography(0-1% EtOAc—hexanes).

¹H NMR (CDCl₃) δ: 7.36 (1H, s), 7.24 (2H, bs), 4.53 (2H, s), 3.11 (1H,septet, J=6.7 Hz), 1.45 (3H, s), 1.22 (6H, d, J=6.7 Hz), 0.85 (2H, m),0.44 (2H, m), 0.25 (9H, s).

4-Ethynyl-2-isopropyl-1-(1-methyl-cyclopropoxymethyl)-benzene(Intermediate 166)

Using General Procedure E;[3-isopropyl-4-(1-methyl-cyclopropoxymethyl)-phenylethynyl]-trimethylsilane(Intermediate 165, 110.0 mg, 0.37 mmol) in methanol (6 mL) was treatedwith potassium carbonate (80.0 mg, 0.58 mmol) and stirred overnight atambient temperature. The crude alkyne (84 mg, 100%) was used directly inthe next reaction.

¹H NMR (CDCl₃) δ: 7.55 (1H, s), 7.41 (2H, m), 4.68 (2H, s), 3.26 (1H,septet, J=6.8 Hz), 3.18 (1H, s), 1.60 (3H, s), 1.37 (6H, d, J=6.8 Hz),0.99 (2H, m), 0.59 (2H, m).

Methyl{4-[3-isopropyl-4-(1-methyl-cyclopropoxymethyl)-phenylethynyl]-phenyl}-acetate(Compound 140, General Formula 6)

Using General Procedure F;4-ethynyl-2-isopropyl-1-(1-methyl-cyclopropoxymethyl)-benzene(Intermediate 166, 78.0 mg, 0.34 mmol) and methyl-(4-iodophenyl)-acetate(Reagent B, 94.0 mg, 0.34 mmol) in triethylamine (8 mL) was treated withcopper(I)iodide (22.0 mg, 0.11 mmol) and sparged with argon for 5minutes. Dichlorobis(triphenylphosphine)palladium(II) (79 mg, 0.11 mmol)was added and the reaction mixture was stirred at room temperature for3.5 hours. Column chromatography (2-5% EtOAc—hexanes) afforded 77.0 mg(60%) of the title compound as a yellow oil.

¹H NMR (CDCl₃) δ: 7.49 (2H, d, J=8.2 Hz), 7.43 (1H, d, J=1.5 Hz),7.33-7.24 (4H, mn), 4.55 (2H, s), 3.70 (3H, s), 3.63 (2H, s), 3.14 (1H,septet, J=6.8 Hz), 1.47 (3H, s), 1.25 (6H, d, J=6.8 Hz), 0.86 (2H, m),0.46 (2H, m).

{4-[3-Isopropyl-4-(1-methyl-cyclopropoxymethyl)-phenylethynyl]-phenyl}-aceticacid (Compound 141, Formula 6)

Using General Procedure I; a solutionmethyl{4-[3-isopropyl-4-(1-methyl-cyclopropoxymethyl)-phenylethynyl]-phenyl}-acetate(Compound 140, 70.0 mg, 0.19 mmol) in ethanol (3 mL) and tetrahydrofuran(3 mL) was treated with NaOH (240.0 mg, 6.0 mmols, 2.0 mL of a 3Naqueous solution) and stirred overnight at room temperature. Work-up andpurification by HPLC (Partisil 10-pac, 10% H₂O/CH₃CN) afforded of thetitle compound as a colorless solid.

¹H NMR (CDCl₃) δ: 7.50 (2H, d, J=8.2 Hz), 7.43 (1H, s), 7.33-7.24 (4H,m), 4.55 (2H, s), 3.65 (2H, s), 3.14 (1H, septet, J=6.7 Hz), 1.47 (3H,s), 1.25 (6H, d, J=6.7 Hz), 0.87 (2H, m), 0.46 (2H, m).

2,6-Di-tert-butyl-4-trimethylsilanylethynyl-phenol: (Intermediate 167)

Following General Procedure D and using 4-bromo-2,6-di-t-butyl-phenol(1.43 g, 5 mmol), triethyl amine (15 mL), anhydrous tetrahydrofuran (15mL), copper(I)iodide (0.06 g, 0.31 mmol), trimethylsilyl acetylene (4.9g, 50 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.18 g,0.26 mmol) followed by flash column chromatography over silica gel(230-400 mesh) using hexane as eluent, the title compound was obtained(1.35 g, 90%).

¹H NMR (300 MHz, CDCl₃): δ7.29 (s, 2H), 5.35 (s, 1H), 1.42 (s, 18H),0.24 (s, 9H).

(3,5-Di-tert-butyl-4-methoxy-phenylethnyl)-trimethyl-silane:(Intermediate 168)

A solution 2,6-di-tert-butyl-4-trimethylsilanylethynyl-phenol(Intermediate 167, 0.302 g, 1 mmol) in acetone (5 mL) was treated withpotassium carbonate (0.138 g, 1 mmol) and methyl iodide (0.142 g, 1mmol) and stirred overnight at room temperature. The volatiles weredistilled off in vacuo and the residue was purified by flash columnchromatography on silica gel (230-400 mesh) using ethyl acetate as theeluent to afford the title compound as a white solid (0.28 g, 90%).

¹H NMR (300 MHz, CDCl₃): δ7.41 (s, 2H), 3.70 (s, 3H), 1.49 (s, 18H),0.30 (s, 9H).

1,3-Di-tert-butyl-5-ethynyl-2-methoxy-benzene: (Intermediate 169)

Following General Procedure E and(3,5-di-tert-butyl-4-methoxy-phenylethynyl)-trimethyl-silane(Intermediate 168, 0.28 g, 0.9 mmol), potassium carbonate (0.98 g, 7.1mmol) and methanol (10 mL) followed by flash column chromatography oversilica gel (230-400 mesh) using hexane as the eluent, the title compoundwas obtained (0.23 g, 100%).

¹H NMR (300 MHz, CDCl₃): δ7.46 (s, 2H), 3.75 (s, 3H), 3.05 (s, 1H), 1.49(s, 18H).

[4-(3,5-Di-tert-butyl-4-methoxy-phenylethynyl)-phenyl]-acetic acidmethyl ester: (Compound 142, General Formula 5)

Following General Procedure F and using1,3-di-tert-butyl-5-ethynyl-2-methoxy-benzene (Intermediate 169, 0.094g, 0.36 mmol), methyl-4-iodo phenyl acetate (Reagent B, 0.09 g, 0.32mmol), triethyl amine (5 mL), anhydrous tetrahydrofuran (5 mL),copper(I)iodide (0.02 g, 0.1 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.06 g, 0.085 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using 10% ethyl acetate in hexane as the eluent, the title compound(0.114 g, 81%) was obtained as an oil.

¹H NMR (300 MHz, CDCl₃): δ7.52 (d, 2H, J=8.0 Hz), 7.46 (s, 2H), 7.28 (d,2H, J=8.2 Hz), 3.72 (s, 3H), 3.71 (s, 3H), 3.66 (s, 2H), 1.47 (s, 18H).

[4-(3,5-Di-tert-butyl-4-methoxy-phenylethynyl)-phenyl]-acetic acid:(Compound 143, General Formula 5)

Following General Procedure I and using[4-(3,5-di-tert-butyl-4-methoxy-phenylethynyl)-phenyl]-acetic acidmethyl ester (Compound 142, 0.114 g, 0.29 mmol), 5M aqueous sodiumhydroxide solution (2 mL) and ethanol (4 mL), followed by preparativereverse phase HPLC using 10% water in acetonitrile as the mobile phase,the title compound was obtained as a white solid (0.097 g, 88%).

¹H NMR (300 MHz, CDCl₃): δ7.55(d, 2H, J=8.0 Hz), 7.48 (s, 2H), 7.30 (d,2H, J=8.2 Hz), 3.74 (s, 3H), 3.69 (s, 2H), 1.49 (s, 18H).

[4-(3,5-Di-tert-butyl-4-methoxy-phenylethynyl)-2-fluoro-phenyl]-aceticacid methyl ester: (Compound 144, General Formula 5)

Following General Procedure F and using1,3-di-tert-butyl-5-ethynyl-2-methoxy-benzene (Intermediate 169, 0.087g, 0.33 mmol), methyl-2-fluoro-4-iodo phenyl acetate (Reagent H, 0.088g, 0.30 mmol), triethyl amine (5 mL), anhydrous tetrahydrofuran (10 mL),copper(I)iodide (0.02 g, 0.1 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.06 g, 0.085 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using 10% ethyl acetate in hexane as the eluent, the title compound(0.122 g, 89%) was obtained.

¹H NMR (300 MHz, CDCl₃): δ7.46 (s, 2H), 7.33-7.24 (m, 3H), 3.75 (s, 3H),3.73(s, 3H), 3.72 (s, 2H), 1.48 (s, 18H).

[4-(3,5-Di-tert-butyl-4-methoxy-phenylethynyl)-2-fluoro-phenyl]-aceticacid: (Compound 145, General Formula 5)

Following General Procedure I and using[4-(3,5-di-tert-butyl-4-methoxy-phenylethynyl)-2-fluoro-phenyl]-aceticacid methyl ester (Compound 144, 0.122 g, 0.29 mmol), 5M aqueous sodiumhydroxide solution (1 mL) and ethanol (4 mL), followed preparativereverse phase HPLC using 10% water in acetonitrile as the mobile phase,the title compound was obtained as a white solid (0.077 g, 65%).

¹H NMR (300 MHz, CDCl₃): δ7.42 (s, 2H), 7.29-7.19 (m, 3H), 3.71 (s, 2H),3.69 (s, 3H), 1.43 (s, 18H).

1. A method identifying a compound which is an inhibitor of the enzymeP450RAI, the method comprising: selecting a compound that has activityas a retinoid in an art recognized assay which demonstratesretinoid-like activity; the retinoid compound including a moietyselected from the group consisting of benzoic acid, benzoic acid ester,naphthoic acid, naphthoic acid ester, heteroaryl carboxylic acid andheteroaryl carboxylic acid ester, with a partial structure of—A(R₂)—(Ch₂)_(n)—COOR₈ where n is 0, A is a phenyl or naphthyl group, orheteroaryl selected from a group consisting of pyridyl, thienyl, furyl,pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl andpyrrazoly, said phenyl, naphthyl and heteroaryl groups being optionallysubstituted with one or two R₂ groups; R₂ is independently H, alkyl of 1of 6 carbons, F, Cl, Br, I, CF₃, fluoro substituted alkyl of 1 of 6carbons, —CH₂O(C₁₋₆-alkyl), or a cation of a pharmaceutically acceptablebase, and further selecting a compound that is a homolog of the selectedretinoid compound where in the formula of the homolog n is 1 or 2 whichcompound is identified as an inhibitor of cytochrome P450RAI.
 2. Amethod in accordance with claim 1 wherein a homolog is selected where inthe formula of the homolog n is
 1. 3. A method in accordance with claim1 further comprising the step of synthesizing the selected homolog.
 4. Amethod in accordance with claim 3 wherein a homolog is synthesized wherein the formula of the homolog n is
 1. 5. A method in accordance withclaim 3 wherein the step of synthesizing the homolog utilizes ahomologation procedure wherein a chain of a carboxylic acid or ofcarboxylic ester of the partial formula —A(R₂)—(CH₂)_(n)—COOR₈ islengthened by adding one or two (CH₂) units.
 6. A method in accordancewith claim 5 wherein the step of synthesizing the homolog utilizesArndt-Eistert method of synthesis.
 7. A method in accordance with claim4 where the step of synthesizing the homolog includes a reaction with areagent selected from the group consisting of the formula set forthbelow